Didepsipeptide-based endoparasiticides, new didepsipeptides and process for preparing the same

ABSTRACT

The present invention relates to the use of didepsipeptides of the general formula (I) and their salts  
                 
 
     in which  
     the radicals have the meaning given in the description, and to new didepsidpeptides and processes for their preparation.

[0001] The present invention relates to the use of didepsipeptides forthe control of endoparasites, to new didepsipeptides and to processesfor their preparation.

[0002] Certain didepsipeptides are, as starting substances forendoparasiticidally active cyclic depsipeptides (cf. total synthesis ofPF 1022 A: JP Pat. 05 229 997; Makoto Ohyama et al., Biosci. Biotech.Biochem. 58 (6), 1994, pp. 1193-1194; Makio Kobayshi et al., Annu. Rep.Sankyo Res. Lab. 46, 1994, pp. 67-75; Stephen J. Nelson et al., J.Antibiotics 47, (11), 1994, pp. 1322-1327; cyclooctadepsipeptides: WO93/19053, EP 0 634 408 A1; WO 94/19334; WO 95/07272; EP 626 375; EP 626376; cyclohexadepsipeptides: DE-OS [German Published Specification] 4342907; WO 93/25543) and open-chain depsipeptides, for exampleoctadepsipeptides (DE-OS [German Published Specification] 4 341 993),hexadepsipeptides (DE-OS [German Published Specification] 4 341 992) ortetradepsipeptides (DE-OS [German Published Specification] 4 341 991),the subject of prior-published patent applications and publications.Some of these abovementioned didepsipeptides are also the subject ofnon-prior-published German Patent Applications (P 44 40 193.0; P 44 01389.2).

[0003] The present invention relates to:

[0004] 1. The use of didepsipeptides of the general formula (I) andtheir salts

[0005]  in which

[0006] R¹ represent hydrogen, straight-chain or branched alkyl,cycloalkyl, arylalkyl, aryl, heteroaryl, heteroarylalkyl, each of whichis optionally substituted,

[0007] R¹ and R² together with the atoms to which they are bondedrepresent a 5- or 6-membered ring which can optionally be interrupted byoxygen, sulphur, sulphoxyl or sulphonyl and is optionally substituted,

[0008] R² and R³ independently of one another represent hydrogen,straight-chain or branched alkyl, alkenyl, cycloalkyl, cycloalkylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, each of which isoptionally substituted, or

[0009] R² and R³ together represent a spirocyclic ring, which isoptionally substituted,

[0010] R⁴ and R⁵ independently of one another represent hydrogen,straight-chain or branched alkyl, alkenyl, cycloalkyl, cycloalkylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, each of which isoptionally substituted, or

[0011] R⁴ and R⁵ together represent a spirocyclic ring, which isoptionally substituted,

[0012] A represents hydrogen, alkyl, aralkyl, formyl, alkoxydicarbonylor a radical of the group G¹

[0013]  in which

[0014]  can denote carboxyl, thiocarboxyl, —CH═CH—NO₂, —CH═CH—CN,—C═N—R⁶, sulphoxyl, sulphonyl, —P(O)—OR⁷ or P(S)—OR⁷,

[0015] R⁶ represents hydrogen, hydroxyl, alkoxy, alkylcarbonyl,halogenoalkylcarbonyl, alkylsulphonyl, nitro or cyano, and

[0016] R⁷ represents hydrogen or alkyl, and

[0017] Q represents straight-chain or branched alkyl, alkenyl, alkinyl,cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl, each of which isoptionally substituted, or optionally represents a radical from thegroup G² and G³

[0018]  in which

[0019]  can denote carboxyl, thiocarboxyl or sulphonyl,

[0020] Y represents oxygen, sulphur or —NR⁹,

[0021] R⁸ in the case where Y represents nitrogen can denote a cyclicamino group linked via a nitrogen atom,

[0022] R⁸ and R⁹ independently of one another represent hydrogen,straight-chain or branched alkyl, alkenyl, alkinyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, hetaryl, hetarylalkyl, each of whichis optionally substituted, or

[0023] R⁸ and R⁹ together with the adjacent N atom [lacuna] acarbocyclic 5-, 6- or 7-membered ring system or a 7 to 10-memberedbicyclic ring system which can optionally also be interrupted by oxygen,sulphur, sulphoxyl, sulphonyl, carbonyl, —N—O—, —N═, —NR¹¹— or byquaternized nitrogen and is optionally substituted,

[0024] R¹⁰ represents hydrogen or alkyl,

[0025] R¹¹ represent represents hydrogen, straight-chain or branchedalkyl, alkenyl, alkinyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl,alkylcarbonyl, cycloalkylcarbonyl, cyano, aryl, arylalkyl, hetaryl,hetarylalkyl, each of which is optionally substituted, and

[0026] B represents hydroxyl, alkoxy, alkenyloxy, alkinyloxy,cycloalkyloxy, cycloalkylalkyloxy, aryloxy-, arylalkyloxy, hetaryloxy,hetarylalkyloxy, each of which is optionally substituted, or

[0027]  represents the radicals —NR¹²R¹³, —NR¹⁴—NR¹²R¹³ and —NR¹⁵—OR¹⁶,

[0028]  in which

[0029] R¹² and R¹³ independently of one another represent hydrogen,straight-chain or branched alkyl, alkylcarbonyl, alkylsulphonyl,alkenyl, alkinyl, cycloalkyl, cycloalkylalkyl, aryl, arylcarbonyl,arylsulphonyl, arylalkyl, hetaryl, hetarylcarbonly, hetarylsulphonyl orhetarylalkyl, each of which is optionally substituted, or

[0030] R¹² and R¹³ together with the adjacent N atom [lacuna] acarbocyclic 5-, 6-, 7- or 8-membered ring system or a 7 to 10-memberedbicyclic ring system which can optionally also be interrupted by oxygen,sulphur, sulphoxyl, sulphonyl, carbonyl, —N—O—, —N═, —NR¹¹— or byquaternized nitrogen and is optionally substituted,

[0031] R¹⁴ represents hydrogen, straight-chain or branched alkyl,cycloalkyl, arylalkyl or hetarylalkyl, each of which is optionallysubstituted,

[0032] R¹⁵ and R¹⁶ independently of one another denote hydrogen,straight-chain or branched alkyl, alkylcarbonyl, alkenyl, alkinyl,cycloalkyl, cycloalkylalkyl, arylalkyl or hetarylalkyl, each of which isoptionally substituted,

[0033] R¹⁵ and R¹⁶ together with the adjacent N—O-group represent acarbocyclic 5-, 6- or 7-membered ring,

[0034] and their optical isomers and racemates,

[0035] for the control of endoparasites in medicine and veterinarymedicine.

[0036] Preferably used didepsipeptides are those of the general formula(I) and their salts

[0037] in which

[0038] R¹ represent hydrogen, straight-chain or branched alkyl having upto 6 carbon atoms, C₃₋₆-cycloalkyl, aryl-C₁₋₂-alkyl or het-C₁₋₂-alkyl,each of which is optionally substituted,

[0039] R¹ and R² together with the atoms to which they are bondedrepresent a 5- or 6-membered ring which can optionally be interrupted bysulphur and is optionally substituted,

[0040] R² and R³ independently of one another represent hydrogen,straight-chain or branched alkyl having up to 6 carbon atoms,halogenoalkyl, hydroxyalkyl, C₁₋₄-alkanoyloxyalkyl, C₁₋₂-alkoxyalkyl,mercaptoalkyl, C₁₋₂-alkylthioalkyl, C₁₋₂-alkylsulphinylalkyl,C₁₋₂-alkylsulphonylalkyl, carboxyalkyl, carbamoylalkyl, aminoalkyl,C₁₋₆-alkylaminoalkyl, C₁₋₆-dialkylaminoalkyl, guanidinoalkyl, which canoptionally be substituted by one or two benzyloxycarbonyl radicals or byone, two, three or four C₁₋₂-alkyl radicals,C₁₋₄-alkoxycarbonylaminoalkyl, C₂₋₆-alkenyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₂-alkyl, and optionally substituted aryl,aryl-C₁₋₂-alkyl, heteroaryl, heteroaryl-C₁₋₂-alkyl, or

[0041] R² and R³ together represent a spirocyclic ring,

[0042] R⁴ and R⁵ independently of one another represent hydrogen,straight-chain or branched alkyl having up to 6 carbon atoms,halogenoalkyl, hydroxyalkyl, C₁₋₄-alkanoyloxyalkyl, C₁₋₂-alkoxyalkyl,mercaptoalkyl, C₁₋₂-alkylthioalkyl, C₁₋₂-alkylsulphinylalkyl,C₁₋₂-alkylsulphonylalkyl, carboxyalkyl, carbamoylalkyl, aminoalkyl,C₁₋₆-alkylaminoalkyl, C₁₋₆-dialkylaminoalkyl, guanidinoalkyl, which canoptionally be substituted by one or two benzyloxycarbonyl radicals or byone, two, three or four C₁₋₂-alkyl radicals,C₁₋₄-alkoxycarbonylaminoalkyl, C₂₋₆-alkenyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₂-alkyl, and optionally substituted aryl,aryl-C₁₋₂-alkyl, heteroaryl, heteroaryl-C₁₋₂alkyl, or

[0043] R⁴ and R⁵ together represent a spirocyclic ring,

[0044] A represents hydrogen, C₁₋₆-alkyl, aryl-C₁₋₂-alkyl, formyl,C₁₋₄-alkoxydicarbonyl or a radical of the group G¹

[0045]  in which

[0046]  can denote carboxyl, thiocarboxyl, —C═CH—NO₂, —C═CH—CN, —C═N—R⁶,sulphoxyl, sulphonyl, —P(O)—OR⁷ or P(S)—OR⁷,

[0047] R⁶ represents hydrogen, hydroxyl, C₁₋₄-alkoxy,C₁₋₄-alkylcarbonyl, C₁₋₄-halogenoalkylcarbonyl, C₁₋₄-alkylsulphonyl,nitro or cyano, and

[0048] R⁷ represents hydrogen or C₁₋₄-alkyl, and

[0049] Q represents straight-chain or branched C₁₋₆-alkyl,C₁₋₆-halogenoalkyl, hydroxy-C₁₋₆-alkyl, C₁₋₄-alkanoyloxy-C₁₋₆-alkyl,C₁₋₂-alkoxy-C₁₋₆-alkyl, mercapto-C₁₋₆-alkyl, C₁₋₂-alkylthio-C₁₋₆-alkyl,C₁₋₂-alkylsulphinyl-C₁₋₆-alkyl, C₁₋₂-alkylsulphonyl-C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, carbamoyl-C₁₋₆-alkyl, amino-C₁₋₆-alkyl,C₁₋₆-alkylamino-C₁₋₆-alkyl, C₁₋₆-dialkylaminoalkyl, C₂₋₆-alkenyl,C₂₋₆-alkinyl, C₂₋₆-halogenoalkenyl, C₃₋₆-cycoalkyl, and optionallysubstituted aryl, aryl-C₁₋₂-aryl, hetaryl or hetaryl-C₁₋₂-alkyl, oroptionally represents a radical from the group G² and G³

[0050] in which

[0051]  can denote carboxyl, thiocarboxyl or sulphonyl,

[0052] Y represents oxygen, sulphur or —NR⁹,

[0053] R⁸ in the case where Y represents nitrogen can denote a cyclicamino group linked via a nitrogen atom,

[0054] R⁸ and R⁹ independently of one another represent hydrogen,straight-chain or branched C₁₋₆-alkyl, C₁₋₆-alkenyl, C₁₋₆-alkinyl,C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₂-alkyl, aryl, arylalkyl, hetaryl,hetarylalkyl, each of which is optionally substituted, or

[0055] R⁸ and R⁹ together with the adjacent N atom [lacuna] acarbocyclic 5-, 6- or 7-membered ring system or a 7 to 10-memberedbicyclic ring system which can optionally also be interrupted by oxygen,sulphur, sulphoxyl, sulphonyl, carbonyl, —N—O, —N═, —NR¹¹— or byquaternized nitrogen and is optionally substituted,

[0056] R¹⁰ represents hydrogen or C₁₋₄-alkyl,

[0057] R¹¹ represents hydrogen, straight-chain or branched C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkinyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₂-alkyl,C₁₋₄-alkoxycarbonyl, C₁₋₄-alkylcarbonyl, C₃₋₆-cycloalkylcarbonyl, cyan,aryl, aryl-C₁₋₂-alkyl, hetaryl, hetaryl-C₁₋₂-alkyl, each of which isoptionally substituted, and

[0058] B represents hydroxyl, C₁₋₆-alkoxy, C₂₋₆-alkenyloxy,C₂₋₆-alkinyloxy, C₃₋₇-cycloalkyloxy, C₃₋₇-cycloalkylalkyloxy, aryloxy-,aryl-C₁₋₂-alkyloxy, hetaryloxy, hetaryl-C₁₋₂-alkyloxy, each of which isoptionally substituted, or

[0059]  represents the radicals —NR¹²R¹³, —NR¹⁴—NR¹²R¹³ and —NR¹⁵—OR¹⁶,

[0060]  in which

[0061] R¹² and R¹³ independently of one another represent hydrogen,straight-chain or branched C₁₋₆-alkyl, C₁₋₆-alkylcarbonyl,C₁₋₆-alkylsulphonyl, C₂₋₆-alkenyl, C₂₋₆-alkinyl, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₂-alkyl, aryl, arylcarbonyl, arylsulphonyl,aryl-C₁₋₂-alkyl, hetaryl, hetarylcarbonyl, hetarylsulphonyl orhetaryl-C₁₋₂-alkyl, each of which is optionally substituted, or

[0062] R¹² and R¹³ together with the adjacent N atom [lacuna] acarbocyclic 5-, 6-, 7- or 8-membered ring system or a 7 to 10-memberedbicyclic ring system, which can optionally also be interrupted byoxygen, sulphur, sulphoxyl, sulphonyl, carbonyl, —N—O—, —N═, —NR¹¹— orby quaternized nitrogen and is optionally substituted,

[0063] R¹⁴ represents hydrogen, straight-chain or branched C₁₋₆-alkyl,C₃₋₆-cycloalkyl, aryl-C₁₋₂-alkyl, hetaryl-C₁₋₂-alkyl, each of which isoptionally substituted,

[0064] R¹⁵ and R¹⁶ independently of one another denote hydrogen,straight-chain or branched C₁₋₆-alkyl, C₁₋₆-alkylcarbonyl, C₂₋₆-alkenyl,C₂₋₆-alkinyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₂-alkyl,aryl-C₁₋₂-alkyl or hetaryl-C₁₋₂-alkyl, each of which is optionallysubstituted,

[0065] R¹⁵ and R¹⁶ together with the adjacent N—O-group represent acarbocyclic 5-, 6- or 7-membered ring,

[0066] and their optical isomers and racemates,

[0067] for the control of endoparasites in medicine and veterinarymedicine.

[0068] The compounds of the formula (I) are known in some cases and canbe prepared analogously to known processes.

[0069] The invention further relates to:

[0070] 2. New didepsipeptides of the general formula (Ia) and theirsalts

[0071]  in which

[0072] R¹ represents hydrogen, straight-chain or branched C₁₋₄-alkyl,C₃₋₆-cyclo-alkyl, aryl-C₁₋₂-alkyl or hetaryl-C₁₋₂-alkyl, each of whichis optionally substituted, and

[0073] R¹ and R² together with the atoms to which they are bondedrepresent a 5- or 6-membered ring which can optionally be interrupted byoxygen, sulphur, sulphoxyl or sulphonyl and is optionally substituted,

[0074] R² represents hydrogen, straight-chain or branched alkyl havingup to 6 carbon atoms, alkenyl having up to 4 carbon atoms,C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₂-alkyl, aryl, aryl-C₁₋₂-alkyl,hetaryl, hetaryl-C₁₋₂-alkyl each of which is optionally substituted,

[0075] R³ and R⁴ represent hydrogen,

[0076] R⁵ represents hydrogen, straight-chain or branched alkyl havingup to 6 carbon atoms, alkenyl having up to 4 carbon atoms,C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₂-alkyl, aryl, aryl-C₁₋₂-alkyl,hetaryl, hetaryl-C₁₋₂-alkyl each of which is optionally substituted,

[0077]  represents carboxyl, thiocarboxyl, —C═CH—NO₂, —C═CH—CN, —C═N—R⁶,sulphoxyl, sulphonyl, —P(O)—OR⁷ or P(S)—OR⁷,

[0078] R⁶ represents hydrogen, hydroxyl, C₁₋₄-alkoxy,C₁₋₄-alkylcarbonyl, C₁₋₄-halogenoalkylcarbonyl, C₁₋₄-alkylsulphonyl,nitro or cyano, and

[0079] R⁷ represents hydrogen or C₁₋₄-alkyl, and

[0080] Q represents straight-chain or branched C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkinyl, C₃₋₆-cycloalkyl or hetaryl-C₁₋₂-alkyl, each of which isoptionally substituted, or optionally represents a radical from thegroup G² and G³

[0081]  in which

[0082]  can denote carboxyl, thiocarboxyl or sulphonyl,

[0083] Y represents oxygen, sulphur or —NR⁹,

[0084] R⁸ in the case where Y represents nitrogen can denote a cyclicamino group linked via a nitrogen atom,

[0085] R⁸ and R⁹ independently of one another represents hydrogen,straight-chain or branched C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkinyl,C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₂-alkyl, hetaryl orhetaryl-C₁₋₂-alkyl, each of which is optionally substituted, or

[0086] R⁸ and R⁹ together with the adjacent N atom represent acarbocyclic 5-, 6- or 7-membered ring system or a 7 to 10-memberedbicyclic ring system which can optionally also be interrupted by oxygen,sulphur, sulphoxyl, sulphonyl, carbonyl, —N—O—, —N═, —NR¹¹— or byquaternized nitrogen and is optionally substituted,

[0087] R¹⁰ represents hydrogen or C₁₋₄-alkyl, and

[0088] R¹¹ represents hydrogen, straight-chain or branched C₁₋₆-alkyl,C₃₋₆-cycloakyl, C₂₋₆-alkenyl, C₂₋₆-alkinyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₂-alkyl, C₁₋₄-alkoxycarbonyl, C₁₋₄-alkylcarbonyl,C₃₋₆-cycloalkylcarbonyl, cyano, aryl, aryl-C₁₋₂-alkyl, hetaryl orhetaryl-C₁₋₂-alkyl, each of which is optionally substituted, and

[0089] B represents C₁₋₆-alkoxy, C₂₋₆-alkenyloxy, C₂₋₆-alkinyloxy,C₃₋₇-cycloalkyloxy, C₃₋₇-cycloalkyl-C₁₋₂-alkyloxy, aryloxy-,aryl-C₁₋₂-alkyloxy, hetaryloxy, hetaryl-C₁₋₂-alkyloxy, each of which isoptionally substituted, or

[0090]  represents the amino radicals —NR¹²R¹³, —NR¹⁴—NR¹²R¹³ and—NR¹⁵—OR¹⁶, in which

[0091] R¹² and R¹³ independently of one another represent hydrogen,straight-chain or branched C₁₋₆-alkyl, C₁₋₆-alkylcarbonyl,C₁₋₆-alkylsulphonyl, C₂₋₆-alkenyl, C₂₋₆-alkinyl, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₂-alkyl, aryl, arylcarbonyl, arylsulphonyl,aryl-C₁₋₂-alkyl, hetaryl, hetarylcarbonyl, hetarylsulphonyl orhetaryl-C₁₋₂-alkyl, each of which is optionally substituted, or

[0092] R¹² and R¹³ together with the adjacent N atom represent acarbocyclic 5-, 6-, 7- or 8-membered ring system or a 7 to 10-memberedbicyclic ring system, which can optionally also be interrupted byoxygen, sulphur, sulphoxyl, sulphonyl, carbonyl, —N—O, —N═, —NR¹¹— or byquaternized nitrogen and is optionally substituted,

[0093] R¹⁴ represents hydrogen, straight-chain or branched C₁₋₆-alkyl,C₃₋₆-cycloalkyl, each of which is optionally substituted,

[0094] R¹⁵ and R¹⁶ independently of one another denote hydrogen,straight-chain or branched C₁₋₆-alkyl, C₁₋₆-alkylcarbonyl, C₂₋₆-alkenyl,C₂₋₆-alkinyl or C₃₋₆-cycloalkyl, each of which is optionallysubstituted, and

[0095] R¹⁵ and R¹⁶ together with the adjacent N—O-group represent acarbocyclic 5-, 6- or 7-membered ring,

[0096] with the proviso in the case where in formula (Ia) R¹, R⁵ and═G═X together represent the following radicals:

[0097] R¹ represents hydrogen and methyl,

[0098] R⁵ represents hydrogen,

[0099]  represents carboxyl,

[0100] the radicals Q and B must fulfil the following condition:

[0101] Q represents radicals other than methyl,

[0102] B represents radicals other than —NH₂,

[0103] and with the proviso in the case where in formula (Ia) G² and═G═X together represent the following radicals:

[0104]  represents carboxyl,

[0105] G² represents tert-butyloxy, benzyloxy and 4-nitro-benzyloxy,

[0106] the radical B represents radicals other than tert-butyloxy,benzyloxy and 4-nitro-benzyloxy,

[0107] and their optical isomers and racemates.

[0108] 3. Process for the preparation of the new didepsipeptides of thegeneral formula (Ia) and their salts,

[0109] in which

[0110] the radicals R¹, R², R³, R⁴, R⁵, G, Q, X and B have the meaningindicated under item 2,

[0111] characterized in that

[0112] a) N-terminal-substituted amino acids of the general formula (II)

[0113]  in which

[0114] the radicals R¹, R², R³, G, Q, and X have the meaning indicatedunder item 2, or their carboxyl-activated derivatives or their alkalimetal salts, are reacted, if appropriate in the presence of a catalyst,if appropriate in the presence of an acid-binding agent and ifappropriate in the presence of a diluent, with carboxylic acidderivatives of the general formula (III)

[0115]  in which

[0116] the radicals R⁴, R⁵ and B have the meaning indicated under item 2and Z represents a suitable leaving group for example halogen such asbromine, chlorine fluorine, or hydroxyl, or

[0117] b) N-terminal-deblocked didepsipeptides of the general formula(Ib)

[0118]  in which

[0119] the radicals R¹, R², R³, R⁴, R⁵ and B have the meaning indicatedunder item 2, are reacted, if appropriate in the presence of a catalyst,if appropriate in the presence of an acid-binding agent and ifappropriate in the presence of a diluent, with compounds of the generalformula (IV)

[0120]  in which

[0121] the radicals G, Q, W and X have the meaning indicated under item2 and W represents a suitable leaving group, for example halogen,alkoxy, alkylthio or aryloxy, or

[0122] c) N-terminal-deblocked didepsipeptides of the general formula(Ib)

[0123]  in which

[0124] the radicals R¹, R², R³, R⁴, R⁵ and B have the meaning indicatedunder item 2, are reacted, if appropriate in the presence of a catalyst,if appropriate in the presence of an acid-binding agent and ifappropriate in the presence of a diluent, with compounds of the generalformulae (V) or (VI)

[0125]  in which

[0126] the radicals R⁸, G¹, X, X¹ and Y have the meaning indicated underitem 2, or

[0127] for the preparation of the depsipeptides of the general formula(Ia) and their salts

[0128] in which the group

[0129]  represents carboxyl and Y represents oxygen,

[0130] d) N-terminal-deblocked didepsipeptides of the general formula(Ib)

[0131]  in which

[0132] the radicals R¹, R², R³, R⁴, R⁵ and B have the meaning indicatedunder item 2,

[0133] are reacted in a first reaction step with carbon dioxide and analkali metal carbonate of the formula (VII)

M₂CO₃  (viI)

[0134]  in which

[0135] M represents a monovalent alkali metal cation, preferablylithium, sodium, potassium or caesium, in particular potassium orcaesium,

[0136] then in a second reaction step the resulting alkali metal salt ofthe formula (VIII)

[0137] in which

[0138] the radicals R¹, R², R³, R⁴, R⁵ and B have the meaning indicatedunder item 2,

[0139] M represents a metal cation equivalent bound like a salt,

[0140] is reacted with alkylating agents of the formula (IX)

R⁸-Hal  (IX)

[0141]  in which

[0142] R⁸ has the meaning indicated under item 2 and

[0143] Hal represents a halogen such as fluorine, chlorine, bromine oriodine,

[0144] if appropriate in the presence of a diluent and if appropriate inthe presence of a basic reaction auxiliary, or

[0145] e) didepsipeptides of the general formula (Ic)

[0146]  in which

[0147] the radicals R¹, R², R³, R⁴, R⁵, G, W, X and B and have themeaning indicated under item 2 and 3b, are reacted, if appropriate inthe presence of a catalyst, if appropriate in the presence of anacid-binding agent and if appropriate in the presence of a diluent, withcompounds of the general formula (X)

R⁸—Y—H  (X)

[0148]  in which

[0149] the radicals R⁸ and Y have the meaning indicated above under item2, or

[0150] f) didepsipeptides of the general formula (Id)

[0151]  in which

[0152] the radicals R¹, R², R³, R⁴, R⁵, G, Q, X and B have the meaningindicated under item 2, or their carboxyl-activated derivatives or theiralkali metal salts are reacted, if appropriate in the presence of acatalyst, if appropriate in the presence of an acid-binding agent and ifappropriate in the presence of a diluent, with compounds of the generalformula (XI)

H—B  (XI)

[0153]  in which

[0154] the radical B has the meaning indicated above under item 2.

[0155] Formula (I) provides a general definition of the substituteddidepsipeptides according to the invention and their salts.

[0156] The substituted didepsipeptides of the formula (I) according tothe invention and their acid addition salts and metal salt complexeshave very good endoparasiticidal, in particular anthelmintic, action andcan preferably be employed in the field of veterinary medicine.

[0157] Optionally substituted alkyl on its own or as a constituent of aradical in the general formulae denotes straight-chain or branched alkylpreferably having 1 to 6, in particular 1 to 4, carbon atoms. Exampleswhich may be mentioned are optionally substituted methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl,1-1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl and2-ethylbutyl. Preferably mention may be made of methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0158] Optionally substituted alkenyl on its own or as a constituent ofa radical in the general formulae denotes straight-chain or branchedalkenyl preferably having 1 to 6, in particular 1 to 4, carbon atoms.Examples which may be mentioned are substituted vinyl, 2-propenyl,2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl,2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-bute-nyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl,2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl,1,2-dimethyl-2-propenyl, 1-ethyl-2-pro-penyl, 2-hexenyl, 3-hexenyl,4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl,3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl,4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl,3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl,1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl,1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl,2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-bute-nyl,1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl,1,1,2-trimethyl-2-prope-nyl, 1-ethyl-1-methyl-2-propenyl and1-ethyl-2-methyl-2-propenyl. Preferably mention may be made ofoptionally substituted ethenyl, 2-propenyl, 2-butenyl or1-methyl-2-propenyl.

[0159] Optionally substituted alkinyl on its own or as a constituent ofa radical in the general formulae denotes straight-chain or branchedalkinyl preferably having 1 to 6, in particular 1 to 4, carbon atoms.Examples which may be mentioned are substituted ethinyl, 2-propinyl,2-butinyl, 3-butinyl, 1-methyl-2-pro-pinyl, 2-pentinyl, 3-pentinyl,4-pentinyl, 1-methyl-3-butinyl, 2-methyl-3-butinyl, 1-me-thyl-2-butinyl,1,1-dimethyl-2-propinyl, 1-ethyl-2-propinyl, 2-hexinyl, 3-hexinyl,4-hexinyl, 5-hexinyl, 1-methyl-2-pentinyl, 1-methyl-3-pentinyl,1-methyl-4-pentinyl, 2-methyl-3-pentinyl, 2-methyl-4-pentinyl,3-methyl-4-pentinyl, 4-methyl-2-pentinyl, 1,1-dimethyl-2-butinyl,1,1-dimethyl-3-butinyl, 1,2-dimethyl-3-butinyl, 2,2-dimethyl-3-bu-tinyl,1-ethyl-3-butinyl, 2-ethyl-3-butinyl and 1-ethyl-1-methyl-2-propinyl.

[0160] Preferably mention may be made of optionally substituted ethinyl,2-propinyl or 2-butinyl.

[0161] Optionally substituted cycloalkyl on its own or as a constituentof a radical in the general formulae denotes mono-, bi- and tricycliccycloalkyl, preferably having 3 to 10, in particular having 3, 5 or 7,carbon atoms. Examples which may be mentioned are substitutedcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl and adamantyl.

[0162] Halogenoalkyl on its own or as a constituent of a radical in thegeneral formulae contains 1 to 4, in particular 1 or 2, carbon atoms andpreferably 1 to 9, in particular 1 to 5, identical or different halogenatoms preferably fluorine, chlorine and bromine, in particular fluorineand chlorine. Examples which may be mentioned are trifluoromethyl,trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl,chloromethyl, bromomethyl, 1-fluoroethyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl,2-chloro-2,2-difluoroethyl, pentafluoroethyl and pentafluoro-tert-butyl.

[0163] Optionally substituted alkoxy on its own or as a constituent of aradical in the general formulae denotes straight-chain or branchedalkoxy preferably having 1 to 6, in particular 1 to 4, carbon atoms.Examples which may be mentioned are optionally substituted methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy andtert-butoxy.

[0164] Optionally substituted halogenoalkoxy on its own or as aconstituent of a radical in the general formulae denotes straight-chainor branched halogenoalkoxy preferably having 1 to 6, in particular 1 to4, carbon atoms. Examples which may be mentioned are optionallysubstituted difluoromethoxy, trifluoromethoxy, trichloromethoxy,chlorodifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy,2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy and2-chloro-1,1,2-trifluoroethoxy.

[0165] Optionally substituted alkylthio on its own or as a constituentof a radical in the general formulae denotes straight-chain or branchedalkylthio preferably having 1 to 6, in particular 1 to 4, carbon atoms.Examples which may be mentioned are optionally substituted methylthio,ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio,sec-butylthio and tert-butylthio.

[0166] Optionally substituted halogenoalkylthio on its own or as aconstituent of a radical in the general formulae denotes straight-chainor branched halogenoalkylthio preferably having 1 to 6, in particular 1to 4, carbon atoms. Examples which may be mentioned are optionallysubstituted difluoromethylthio, trifluoromethylthio,trichloromethylthio, chlorodifluoromethylthio, 1-fluoroethylthio,2-fluoroethylthio, 2,2-di-fluoroethylthio, 1,1,2,2-tetrafluoroethylthio,2,2,2-trifluoroethylthio and 2-chloro-1,1,2-trifluoroethylthio.

[0167] Optionally substituted alkylcarbonyl on its own or as aconstituent of a radical in the general formulae denotes straight-chainor branched alkylcarbonyl having 1 to 6, in particular 1 to 4, carbonatoms. Examples which may be mentioned are optionally substitutedmethylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl,n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl andtert-bu-tylcarbonyl.

[0168] Optionally substituted cycloalkylcarbonyl on its own or as aconstituent of a radical in the general formulae denotes mono-, bi- andtricyclic cycloalkylcarbonyl, preferably having 3 to 10, in particularhaving 3, 5 or 7, carbon atoms. Examples which may be mentioned areoptionally substituted cyclopropylcarbonyl, cyclobutylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl,cyclooctylcarbonyl, bicyclo[2.2.1]heptylcarbonyl,bicyclo[2.2.2]octylcarbonyl and adamantylcarbonyl.

[0169] Optionally substituted alkoxycarbonyl on its own or as aconstituent of a radical in the general formulae denotes straight-chainor branched alkoxycarbonyl preferably having 1 to 6, in particular 1 to4, carbon atoms. Examples which may be mentioned are optionallysubstituted methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl and tert-butoxycarbonyl.

[0170] Aryl is, for example, a mono-, bi- or polynuclear aromaticradical such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, fluorenyland the like, preferably phenyl or naphthyl.

[0171] Optionally substituted aryl in the general formulae denotesphenyl or naphthyl which is preferably optionally substituted, inparticular phenyl.

[0172] Optionally substituted arylalkyl in the general formulae denotesarylalkyl which is preferably optionally substituted in the aryl moietyand/or alkyl, preferably having 6 or 10, in particular 8, carbon atomsin the aryl moiety (preferably phenyl or naphthyl, in particular phenyl)and preferably 1 to 4, in particular 1 or 2, carbon atoms in the alkylmoiety, where the alkyl moiety can be straight-chain or branched.Examples which may preferably be mentioned are optionally substitutedbenzyl and phenylethyl.

[0173] Optionally substituted hetaryl on its own or as a constituent ofa radical in the general formulae denotes 5- to 7-membered ringspreferably having 1 to 3, in particular 1 or 2, identical or differentheteroatoms. Heteroatoms in the heteroaromatics are oxygen, sulphur ornitrogen. Examples which may preferably be mentioned are optionallysubstituted furyl, thienyl, pyrazolyl, imid-azolyl, 1,2,3- and1,2,4-triazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-, 1,3,4-,1,2,4- and 1,2,5-oxadiazolyl, azepinyl, piperidyl, pyrrolyl, pyridyl,piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-, 1,2,4- and1,2,3-triazinyl, 1,2,4-, 1,3,2-, 1,3,6- and 1,2,6-oxazinyl, oxepinyl,thiepinyl and 1,2,4-diazepinyl.

[0174] The optionally substituted radicals of the general formulae cancarry one or more, preferably 1 to 3, in particular 1 or 2, identical ordifferent substituents. Examples of substituents which may preferably bementioned are:

[0175] alkyl preferably having 1 to 4, in particular 1 to 2, carbonatoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl and tert-butyl; alkoxy preferably having 1 to 4, in particular1 to 2 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy and tert-butoxy; alkylthio such asmethylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio,isobutylthio, sec-butylthio and tert-butylthio; halogenoalkyl preferablyhaving 1 to 4, in particular 1 to 2 carbon atoms and preferably 1 to 5,in particular 1 to 3, halogen atoms, where the halogen atoms areidentical or different and, as halogen atoms, are preferably fluorine,chlorine or bromine, in particular fluorine or chlorine, such asdifluoromethyl, trifluoromethyl, trichloromethyl; hydroxyl; halogen,preferably fluorine, chlorine, bromine and iodine, in particularfluorine and chlorine; cyano; nitro; ami-no; monoalkyl- and dialkylaminopreferably having 1 to 4, in particular 1 or 2 carbon atoms per alkylgroup, such as methylamino, methylethylamino, dimethyl-amino,n-propyl-amino, isopropylamino, methyl-n-butylamino; alkylcarbonylradicals such as methylcarbonyl; alkoxycarbonyl preferably having 2 to4, in particular 2 to 3, carbon atoms, such as methoxycarbonyl andethoxycarbonyl; alkylsulphinyl having 1 to 4, in particular 1 to 2,carbon atoms; halogenosulphinyl having 1 to 4, in particular 1 to 2,carbon atoms and 1 to 5 halogen atoms, such as trifluoromethylsilphinyl;sulphonyl (—SO₂—OH); alkylsulphonyl preferably having 1 to 4, inparticular 1 or 2, carbon atoms, such as methylsulphonyl andethylsulphonyl; halogenoalkylsulphonyl having 1 to 4, in particular 1 to2, carbon atoms and 1 to 5 halogen atoms, such astrifluoromethylsulphonyl, perfluoro-n-butylsulphonyl,perfluoroisobutylsulphonyl; arylsulphonyl preferably having 6 or 10 arylcarbon atoms, such as phenylsulphonyl; acyl, aryl, aryloxy, hetaryl,hetaryloxy, which for their part can carry one of the abovementionedsubstituents, and the formimino radical (—HC═N—O-alkyl).

[0176] Suitable cyclic amino groups are heteroaromatic or aliphatic ringsystems having one or more nitrogen atoms as heteroatom, in which theheterocycles can be saturated or unsaturated, a ring system or severalfused ring systems, and optionally contain further heteroatoms such asnitrogen, oxygen and sulphur etc. Additionally, cyclic amino groups canalso denote a spiro ring or a bridged ring system. The number of atomswhich form cyclic amino groups is not restricted, for example theyconsist in the case of a one-ring system of 3 to 8 atoms and in the caseof a three-ring system of 7 to 11 atoms.

[0177] Examples of cyclic amino groups having saturated and unsaturatedmonocyclic groups having a nitrogen atom as heteroatom which may bementioned are 1-azetidinyl, pyr-rolidino, 2-pyrrolin-1-yl, 1-pyrrolyl,piperidino, 1,4-dihydropyridin-1-yl, 1,2,5,6-tetrahydropyridin-1-yl,homopiperidino; examples of cyclic amino groups having saturated andunsaturated monocyclic groups having two or more nitrogen atoms asheteroatoms which may be mentioned are 1-imidazolidinyl, 1-imidazolyl,1-pyrazolyl, 1-triazolyl, 1-tetrazolyl, 1-piperazinyl,1-homopiperazinyl, 1,2-dihydro-pyridazin-1-yl,1,2-dihydropyrimidin-1-yl, perhydropyrimidin-1-yl and1,4-diazacycloheptan-1-yl; examples of cyclic amino groups havingsaturated and unsaturated monocyclic groups having one to three nitrogenatoms and one to two sulphur atoms as heteroatoms which may be mentionedare thiazolidin-3-yl, isothiazolin-2-yl, thiomorpholino ordioxothiomorpholino; examples of cyclic amino groups having saturatedand unsaturated fused cyclic groups which may be mentioned areindol-1-yl, 1,2-dihydrobenzimidazol-1-yl,perhydropyrrolo[1,2-a]pyrazin-2-yl; an example of cyclic amino groupshaving spirocyclic groups which may be mentioned is2-azaspiro[4,5]decan-2-yl; an example of cyclic amino group-bridgedheterocyclic groups which may be mentioned is2-azabicyclo[2,2,1]heptan-7-yl.

[0178] Preferred compounds are those of the formula (Ia) and their salts

[0179] in which

[0180] R¹ represents hydrogen, straight-chain or branched C₁₋₆-alkyl, inparticular methyl, ethyl, propyl, isopropyl, sec-butyl, tert-butyl,C₃₋₆-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, aryl-C₁₋₂-alkyl, in particular phenylmethyl orhetaryl-C₁₋₂-alkyl, in particular pyridylmethyl and thiazolylmethyl,each of which is optionally substituted, and

[0181] R¹ and R² together with the atoms to which they are bondedrepresent a 5- or 6-membered ring which can optionally be interrupted bysulphur and is optionally substituted by hydroxyl,

[0182] R² represents hydrogen, straight-chain or branched alkyl havingup to 6 carbon atoms, in particular methyl, ethyl, propyl, isopropyl,sec-butyl, tert-butyl, hydroxy-C₁₋₂-alkyl, in particular hydroxymethyl,1-hydroxyethyl, C₁₋₄-alkanoyloxy-C₁₋₄-alkyl, in particularacetoxymethyl, 1-acetoxyethyl, C₁₋₄-alkoxy-C₁₋₄-alkyl, in particularmethoxymethyl, 1-methoxyethyl, aryl-C₁₋₄-alkoxy-C₁₋₄-alkyl, inparticular benzyloxymethyl, 1-benzyloxymethyl, mercapto-C₁₋₄-alkyl, inparticular mercaptomethyl, C₁₋₄-alkylthio-C₁₋₄-alkyl, in particularmethylsulphinylmethyl, C₁₋₄-alkylsulphonyl-C₁₋₄-alkyl, in particularmethylsulphonylethyl, carboxy-C₁₋₄-alkyl, in particular carboxymethyl,carboxyethyl, C₁₋₄-alkoxycarbonyl-C₁₋₄-alkyl, in particularmethoxycarbonylmethyl, ethoxycarbonylmethyl,aryl-C₁₋₄-alkoxycarbonyl-C₁₋₄-alkyl, in particularbenzyloxycarbonylmethyl, carbamoyl-C₁₋₄-alkyl, in particularcarbamoylmethyl, carbamoylethyl, amino-C₁₋₄-alkyl, in particularaminopropyl, aminobutyl, C₁₋₄-alkylamino-C₁₋₄-alkyl, in particularmethylaminopropyl, methylaminobutyl, C₁₋₄-dialkylamino-C₁₋₄-alkyl, inparticular dimethylaminopropyl, dimethylaminobutyl, guanido-C₁₋₄-alkyl,in particular guanidopropyl, C₁₋₄-alkoxycarbonylamino-C₁₋₄-alkyl, inparticular tert-butylcarbonylaminopropyl, tert-butylcarbonylaminobutyl,alkenyl having up to 6 carbon atoms, in particular vinyl, 2-propenyl,2-butenyl, 1-methyl-2-propenyl, C₃₋₆-cycloalkyl-C₁₋₂-alkyl, inparticular cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl,hetaryl-C₁₋₂-alkyl, in particular benzo-[b]thien-1-yl-methyl,benzo[b]-thien-3-yl, pyrid-2-yl-methyl, pyrid-3-yl-methyl,pyrid-4-yl-methyl, fur-2-yl-methyl, fur-3-yl-methyl, thien-2-yl-methyl,thien-3-yl-methyl, indol-3-yl-methyl, N-methyl-indol-3-yl-methyl,imidazol-4-yl-methyl, N-methylimidazol-4-yl-methyl, aryl-C₁₋₂-alkyl, inparticular benzyl, each of which can optionally be substituted byradicals from the series consisting of halogen, in particular, fluorine,chlorine, bromine or iodine, hydroxyl, C₁₋₄-alkyl, in particular methylor tert-butyl, C₁₋₄-halogenoalkyl, in particular trifluoromethylethyl,difluoromethyl or trichloromethyl, C₁₋₄-alkoxy, in particular methoxy,ethoxy or tert-butyloxy, C₁₋₄-halogenoalkoxy, in particularTrifluoromethoxy, difluoromethoxy, C₁₋₄-alkylthio, in particularmethylthio, C₁₋₄-halogenoalkylthio, in particular trifluoromethylthio,C₁₋₂-alkylenedioxy, in particular methylenedioxy or ethylenedioxy,nitro, amino, C₁₋₄-alkylamino, in particular methylamino,C₁₋₄-di-alkylamino, in particular dimethylamino, C₃₋₆-cycloalkylamino,in particular pyrrolidino, piperidino, C₃₋₆-cycloalkylthioamino, inparticular thiomorpholino and dioxothiomorpholino,C₃₋₆-cycloalkyldiamino, in particular N-methylpiperazino, and

[0183] R³ and R⁴ represent hydrogen,

[0184] R⁵ represents hydrogen, straight-chain or branched alkyl havingup to 6 carbon atoms, in particular methyl, ethyl, propyl, isopropyl,sec-butyl, tert-butyl, hydroxy-C₁₋₂-alkyl, in particular hydroxymethyl,1-hydroxyethyl, C₁₋₄-alkanoyloxy-C₁₋₄-alkyl, in particularacetoxymethyl, 1-acetoxyethyl, C₁₋₄-alkoxy-C₁₋₄-alkyl, in particularmethoxymethyl, 1-methoxyethyl, aryl-C₁₋₄-alkoxy-C₁₋₄-alkyl, inparticular benzyloxymethyl, 1-benzyloxymethyl, mercapto-C₁₋₄-alkyl, inparticular mercaptomethyl, C₁₋₄-alkylthio-C₁₋₄-alkyl, in particularmethylsulphinylmethyl, C₁₋₄-alkylsulphonyl-C₁₋₄-alkyl, in particularmethylsulphonylethyl, carboxy-C₁₋₄-alkyl, in particular carboxymethyl,carboxyethyl, C₁₋₄-alkoxycarbonyl-C₁₋₄-alkyl, in particularmethoxycarbonylmethyl, ethoxycarbonylmethyl,aryl-C₁₋₄-alkoxycarbonyl-C₁₋₄-alkyl, in particularbenzyloxycarbonylmethyl, carbamoyl-C₁₋₄-alkyl, in particularcarbamoylmethyl, carbamoylethyl, amino-C₁₋₄-alkyl, in particularaminopropyl, aminobutyl, C₁₋₄-alkylamino-C₁₋₄-alkyl, in particularmethylaminopropyl, methylaminobutyl, C₁₋₄-dialkylamino-C₁₋₄-alkyl, inparticular dimethylaminopropyl, dimethylaminobutyl, guanido-C₁₋₄-alkyl,in particular guanidopropyl, C₁₋₄-alkoxycarbonylamino-C₁₋₄-alkyl, inparticular tert-butylcarbonylaminopropyl, tert-butylcarbonylaminobutyl,alkenyl having up to 6 carbon atoms, in particular vinyl, 2-propenyl,2-butenyl, 1-methyl-2-propenyl, C₃₋₆-cycloalkyl-C₁₋₂-alkyl, inparticular cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl,hetaryl-C₁₋₂-alkyl, in particular benzo-[b]thien-1-yl-methyl,benzo[b]-thien-3-yl, pyrid-2-yl-methyl, pyrid-3-yl-methyl,pyrid-4-yl-methyl, fur-2-yl-methyl, fur-3-yl-methyl, thien-2-yl-methyl,thien-3-yl-methyl, indol-3-yl-methyl, N-methyl-indol-3-yl-methyl,imidazol-4-yl-methyl, N-methylimidazol-4-yl-methyl, aryl-C₁₋₂-alkyl, inparticular benzyl, each of which can optionally be substituted byradicals from the series consisting of halogen, in particular fluorine,chlorine, bromine or iodine, hydroxyl, C₁₋₄-alkyl, in particular methylor tert-butyl, C₁₋₄-halogenoalkyl, in particular trifluoromethylethyl,difluoromethyl or trichloromethyl, C₁₋₄-alkoxy, in particular methoxy,ethoxy or tert-butyloxy, C₁₋₄-halogenoalkoxy, in particulartrifluoromethoxy, difluoromethoxy, C₁₋₄-alkylthio, in particularmethylthio, C₁₋₄-halogenoalkylthio, in particular trifluoromethylthio,C₁₋₂-alkylenedioxy, in particular methylenedioxy or ethylenedioxy,nitro, amino, C₁₋₄-alkylamino, in particular methylamino,C₁₋₄-dialkylamino, in particular dimethylamino, C₃₋₆-cycloalkylamino, inparticular pyrrolidino, piperidino, C₃₋₆-cycloalkylthioamino, inparticular thiomorpholino and dioxothiomorpholino,C₃₋₆-cycloalkyldiamino, in particular N-methylpiperazino, and

[0185]  represents carboxyl, thiocarboxyl, —CH═CH—NO₂, —C═CH—CN,—C═N—R⁶,

[0186] sulphoxyl, sulphonyl, —P(O)—OR⁷ or P(S)—OR⁷,

[0187] R⁶ represents hydrogen, hydroxyl, C₁₋₄-alkoxy, in particularmethoxy, ethoxy, sec-butyloxy, C₁₋₄-alkylcarbonyl, in particularmethylcarbonyl, ethylcarbonyl, C₁₋₄-halogenoalkylcarbonyl, in particulartrifluoromethylcarbonyl, trichloromethylcarbonyl, C₁₋₄-alkylsulphonyl,in particular methylsulphonyl, ethylsulphonyl, propylsulphonyl, nitro orcyano, and

[0188] R⁷ represents hydrogen or C₁₋₄-alkyl, in particular methyl orethyl, and

[0189] Q represents straight-chain or branched C₁₋₄-alkyl, in particularmethyl, ethyl, propyl, isopropyl, sec-butyl, tert-butyl,C₁₋₄-halogenoalkyl, in particular trifluoromethyl, trichloromethyl,chlorodifluoromethyl, dichlorofluoromethyl, 1-fluoroethyl, chloromethyl,bromomethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl,C₂₋₆-alkenyl, in particular vinyl, 2-propenyl, 1-methyl-2-propenyl and2-butenyl, C₂₋₆-halogenoalkenyl, in particular difluorovinyl,dichlorovinyl, 2-chloro-2-propenyl, 2,3,3-trifluoro-2-propenyl,2,3,3-trichloro-2-propenyl, 4,4-difluoro-3-butenyl, C₃₋₆-cycloalkyl, inparticular cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,hetaryl-C₁₋₂-alkyl, in particular pyridylmethyl and thiazolylmethyl,each of which can optionally be substituted by radicals from the seriesconsisting of halogen, in particular fluorine, chlorine, bromine oriodine, hydroxyl, C₁₋₄-alkyl, in particular methyl or tert-butyl,C₁₋₄-halogenoalkyl, in particular trifluoromethyl, difluoromethyl ortrichloromethyl, C₁₋₄-alkoxy, in particular methoxy,C₁₋₄-halogenoalkoxy, in particular trifluoromethoxy, difluoromethoxy,C₁₋₄-alkylthio, in particular methylthio, C₁₋₄-halogenoalkylthio, inparticular trifluoromethylthio, nitro, amino, C₁₋₄-alkylamino, inparticular methylamino, C₁₋₄-dialkylamino, in particular dimethylamino,or

[0190] optionally represents a radical from the group G² and G³

[0191]  in which

[0192]  can denote carboxyl, thiocarboxyl or sulphonyl,

[0193] Y represents oxygen, sulphur or —NR⁹,

[0194] R⁸ in the case where Y represents nitrogen [lacuna] a cyclicamino group linked via a nitrogen atom, in particular 1-azetidinyl,pyrrolidino, 2-pyrrolin-1-yl, 1-pyrrolyl, piperidino,1,4-dihydropyridin-1-yl, 1-imidazolidiyl, 1-imidazolyl, 1-pyrazolyl,1-triazolyl, 1-tetrazolyl, 1-piperazinyl, 1-homopiperazinyl,1,2-dihydro-pyridazin-1-yl, 1,2-dihydropyrimidin-1-yl,perhydropyrimidin-1-yl, 1,4-diazacyclo-heptan-1-yl, thiazolidin-3-yl,isothiazolin-2-yl, morpholino, thiomorpholino, dioxothiomorpholino, eachof which is optionally substituted by radicals from the seriesconsisting of halogen, in particular fluorine, chlorine, bromine oriodine, C₁₋₄-alkyl, in particular methyl, hydoxy-C₁₋₄-alkyl, inparticular hydroxymethyl, amino-C₁₋₄-alkyl, in particular aminomethyl,aminoethyl, C₁₋₄-monoalkylamino-C₁₋₄-alkyl, in particularmethylaminomethyl, methylaminoethyl, C₁₋₄-dialkylamino-C₁₋₄-alkyl, inparticular dimethylaminomethyl, dimethylaminoethyl, amino, hydroxyl,C₁₋₄-alkoxy, in particular methoxy, C₁₋₄-alkylcarbonyl, in particularmethylcarbonyl, C₁₋₄-alkoxycarbonyl, in particular methoxycarbonyl,

[0195] R⁸ and R⁹ independently of one another represent hydrogen,straight-chain or branched C₁₋₄-alkyl, in particular methyl, ethyl,propyl, isopropyl, sec-butyl, tert-butyl, C₂₋₄-alkenyl, in particularvinyl, 2-propenyl, 1-methyl-2-propenyl and 2-butenyl, C₂₋₄-alkinyl, inparticular ethinyl, 2-propinyl and 2-butinyl, C₃₋₆-cycloalkyl, inparticular cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,C₃₋₆-cycloalkyl-C₁₋₂-alkyl, in particular cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl, hetaryl, inparticular pyridyl and thiazolyl, hetaryl-C₁₋₂-alkyl, in particularpyridylmethyl and thiazolylmethyl, each of which can optionally besubstituted by radicals from the series consisting of halogen, inparticular fluorine, chlorine, bromine or iodine, C₁₋₄-alkyl, inparticular methyl, hydoxy-C₁₋₄-alkyl, in particular hydroxymethyl,amino-C₁₋₄-alkyl, in particular aminomethyl, aminoethyl,C₁₋₄-monoalkylamino-C₁₋₄-alkyl, in particular methylaminomethyl,methylaminoethyl, C₁₋₄-dialkylamino-C₁₋₄-alkyl, in particulardimethylaminomethyl, dimethylaminoethyl, amino, hydroxyl, C₁₋₄-alkoxy,in particular methoxy, C₁₋₄-alkylcarbonyl, in particular methylcarbonyl,C₁₋₄-alkoxycarbonyl, in particular methoxycarbonyl, or

[0196] R⁸ and R⁹ together with the adjacent N atom represent acarbocyclic 5-, 6- or 7-membered ring system or a 7 to 10-memberedbicyclic ring system which can optionally also be interrupted by oxygen,sulphur, sulphoxyl, sulphonyl, carbonyl, —N—O, —N═, —NR¹¹— or byquaternized nitrogen and is optionally substituted by C₁₋₄-alkyl, inparticular methyl, hydoxy-C₁₋₄-alkyl, in particular hydroxymethyl,amino-C₁₋₄-alkyl, in particular aminomethyl, aminoethyl,C₁₋₄-monoalkylamino-C₁₋₄-alkyl, in particular methylaminomethyl,methylaminoethyl, C₁₋₄-dialkylamino-C₁₋₄-alkyl, in particulardimethylaminomethyl, dimethylaminoethyl, amino, hydroxyl, C₁₋₄-alkoxy,in particular methoxy, C₁₋₄-alkylcarbonyl, in particular methylcarbonyl,C₁₋₄-alkoxycarbonyl, in particular methoxycarbonyl, halogen, inparticular fluorine, chlorine, bromine or iodine,

[0197] R¹⁰ represents hydrogen or C₁₋₄-alkyl, in particular methyl,ethyl, propyl, isopropyl, sec-butyl, tert-butyl, and

[0198] R¹¹ represents hydrogen, straight-chain or branched C₁₋₆-alkyl,in particular methyl, ethyl, propyl, isopropyl, sec-butyl, tert-butyl,C₂₋₆-alkenyl, in particular vinyl, 2-propenyl, 1-methyl-2-propenyl and2-butenyl, C₂₋₆-alkinyl, in particular ethinyl, 2-propinyl and2-butinyl, C₃₋₆-cycloalkyl, in particular cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl, C₃₋₆-cycloalkyl-C₁₋₂-alkyl, in particularcyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl andcyclohexylmethyl, C₁₋₄-alkylcarbonyl, in particular methylcarbonyl,ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl,isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl,C₃₋₆-cycloalkylcarbonyl, in particular cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl,C₁₋₄-alkoxycarbonyl, in particular methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl,hydoxy-C₁₋₄-alkyl, in particular hydroxymethyl, hydroxyethyl,hydroxyethylsulphonylethyl, C₁₋₄-alkylamino, in particular methylamino,ethylamino, C₁₋₄-monoalkylamino-C₁₋₄-alkyl, in particularmethylaminomethyl, methylaminoethyl, C₁₋₄-dialkylamino-C₁₋₄-alkyl, inparticular dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,C₃₋₇-cycloalkylamino-C₁₋₄-alkyl, in particular N-pyrrolidinoethyl,N-morpholinoethyl, N-piperidinoethyl, N-thiomorpholinoethyl,N¹-(N⁴-methylpiperazino)ethyl, C₃₋₆-cycloalkylaminocarbonyl-C₁₋₂-alkyl,in particular N-morpholinocarbonylmethyl, cyano, aryl, in particularphenyl, aryl-C₁₋₂-alkyl, in particular phenylmethyl, hetaryl, inparticular pyridyl or thiazolyl, hetaryl-C₁₋₂-alkyl, in particularpyridylmethyl and thiazolylmethyl, each of which can optionally besubstituted by radicals from the series consisting of halogen, inparticular fluorine, chlorine, bromine or iodine, C₁₋₄-alkyl, inparticular methyl, C₁₋₄-halogenoalkyl, in particular trifluoromethyl,trichloromethyl, amino, hydroxyl, C₁₋₄-alkoxy, in particular methoxy,C₁₋₂-alkylenedioxy, in particular methylenedioxy or ethylenedioxy,C₁₋₄-halogenoalkoxy, in particular trifluoromethoxy, difluoromethoxy,C₁₋₄-alkylthio, in particular methylthio, C₁₋₄-halogenoalkylthio, inparticular trifluoromethylthio, C₁₋₄-alkylsulphonyl in particularmethylsulphonyl, C₁₋₄-alkylamino, in particular methylamino,di-C₁₋₄-alkylamino, in particular dimethylamino, C₁₋₄-alkylcarbonyl, inparticular methylcarbonyl, C₁₋₄-alkoxycarbonyl, in particularmethoxycarbonyl

[0199] B represents straight-chain or branched C₁₋₆-alkoxy, inparticular methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,sec-butoxy and tert-butoxy, C₂₋₆-alkenyloxy, vinyloxy, 2-propenyloxy,2-butenyloxy, 3-butenyloxy, 1-methyl-2-propenyloxy,2-methyl-2-propenyloxy, 2-pentenyloxy, 1-methyl-2-butenyloxy,2-methyl-2-butenyloxy, 3-methyl-2-butenyloxy, 1-methyl-3-butenyloxy,1,1-dimethyl-2-propenyloxy, 1,2-dimethyl-2-propenyloxy,1-ethyl-2-propenyloxy, 2-hexenyloxy, 1,1-dimethyl-2-butenyloxy,1,2-dimethyl-2-butenyloxy, 1-ethyl-2-butenyloxy, C₂₋₆-alkinyloxy, inparticular ethinyloxy, 2-propinyloxy, 2-butinyloxy, 3-butinyloxy,1-methyl-2-propinyloxy, 2-pentinyloxy, 1-methyl-3-butinyl,2-methyl-3-butinyloxy, 1,1-dimethyl-2-propinyloxy, 1-ethyl-2-propinyloxyand 1-methyl-2-pentinyloxy, C₃₋₈-cycloalkyloxy, in particularcyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy,cycloheptyloxy, C₃₋₇-cycloalkyl-C₁₋₂-alkyloxy, in particularcyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy,cyclohexylmethoxy, cycloheptylmethoxy, aryloxy-, in particular phenoxy,aryl-C₁₋₂-alkyloxy, in particular benzyloxy, hetaryloxy, in particularpyridyloxy, hetaryl-C₁₋₂-alkyl-oxy, in particular pyridylmethyl andthiazolylmehyl, each of which can optionally be substituted by radicalsfrom the series consisting of halogen, in particular fluorine, chlorine,bromine or iodine, C₁₋₄-alkyl, in particular methyl, C₁₋₄-halogenoalkyl,in particular trifluoromethyl, trichloromethyl, amino, hydroxyl,C₁₋₄-alkoxy, in particular methoxy, C₁₋₂-alkylenedioxy, in particularmethylenedioxy or ethylenedioxy,C₁₋₄-halogenoalkoxy, in particulartrifluoromethoxy, difluoromethoxy, C₁₋₄-alkylthio, in particularmethylthio, C₁₋₄-halogenoalkylthio, in particular trifluoromethylthio,C₁₋₄-alkylsulphonyl in particular methylsulphonyl, C₁₋₄-alkylamino, inparticular methylamino, di-C₁₋₄-alkylamino, in particular dimethylamino,C₃₋₆-cycloalkylamino, in particular pyrrolidino, piperidino,C₃₋₆cycloalkyloxamino, in particular morpholino,C₃₋₆-cycloalkylthioamino, in particular thiomorpholino anddioxothiomorpholino, C₃₋₆-cycloalkyldiamino, in particularN-methylpiperazino, C₁₋₄-alkylcarbonyl, in particular methylcarbonyl,C₁₋₄-alkoxycarbonyl, in particular methoxycarbonyl, or

[0200]  represents the amino radicals —NR¹²R¹³, —NR¹⁴—NR¹²R¹³ and—NR¹⁵—OR¹⁶,

[0201]  in which

[0202] R¹² and R¹³ independently of one another represent hydrogen,straight-chain or branched C₁₋₆-alkyl, in particular methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl,1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl,1-methylpentyl, C₁₋₆-alkylcarbonyl, in particular methylcarbonyl,ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl,isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl,1-methylbutylcarbonyl, 2-methylbutylcarbonyl, C₁₋₆-alkylsulphonyl, inparticular methylsulphonyl, ethylsulphonyl, n-propylsulphonyl,isopropylsulphonyl, n-butylsulphonyl, isobutylsulphonyl,sec-butylsulphonyl, C₂₋₆-alkenyl, in particular vinyl, 2-propenyl,2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-pentenyl, 3-pentenyl,1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-pro-penyl,2-hexenyl, 1,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl,1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl,2-ethyl-3-butenyl, C₂₋₆-alkinyl, in particular 2-propinyl, 2-butinyl,3-butinyl, C₃₋₈-cycloalkyl, in particular cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,C₃₋₈-cycloalkyl-C₁₋₂-alkyl, in particular cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,cycloheptylmethyl, hydoxy-C₁₋₄-alkyl, in particular hydroxymethyl,hydroxyethyl, hydroxyethylsulphonylethyl, C₁₋₄-alkylamino, in particularmethylamino, ethylamino, C₁₋₄-monoalkylamino-C₁₋₄-alkyl, in particularmethylaminomethyl, methylaminoethyl, methylaminopropyl,C₁₋₄-dialkylamino-C₁₋₄-alkyl, in particular dimethylaminomethyl,dimethylaminoethyl, dimethylaminopropyl,C₃₋₇-cycloalkylamino-C₁₋₄-alkyl, in particular N-pyrrolidinoethyl,N-morpholinoethyl, N-piperidinoethyl, N-thiomorpholinoethyl,N¹-(N⁴-methyl-piperazino)-ethyl, C₃₋₆cycloalkylaminocarbonyl-C₁₋₂-alkyl,in particular N-morpholinocarbonylmethyl, aryl, in particular phenyl,aryl-C₁₋₂-alkyl, in particular benzyl and phenethyl, hetaryl, inparticular pyridyl, thiazolyl, hetaryl-C₁₋₆-alkyl, in particularpyridylmethyl, thiazolylmethyl, each of which is optionally substitutedby radicals from the series consisting of halogen, in particularfluorine, chlorine, bromine or iodine, hydroxyl, C₁₋₄-alkyl, inparticular methyl or tert-butyl, C₁₋₄-alkoxy, in particular methoxy,ethoxy or tert-butyloxy, nitro, amino, C₁₋₄-alkylamino, in particularmethylamino, C₁₋₄-dialkylamino, in particular dimethylamino,C₃₋₆-cycloalkylamino, in particular piperidino and morpholine or

[0203] R¹² and R¹³ together with the adjacent N atom represent acarbocyclic 5-, 6-, 7- or 8-membered ring system or a 7 to 10-memberedbicyclic ring system which can optionally also be interrupted by oxygen,sulphur, sulphoxyl, sulphonyl, carbonyl, —N—O—, —N═, —NR¹¹— or byquaternized nitrogen and is optionally substituted by aryl, inparticular phenyl, C₁₋₄-alkyl, in particular methyl, hydoxy-C₁₋₄-alkyl,in particular hydroxymethyl, amino-C₁₋₄-alkyl, in particularaminomethyl, aminoethyl, C₁₋₄-monoalkylamino-C₁₋₄-alkyl, in particularmethylaminomethyl, methylaminoethyl, C₁₋₄-dialkylamino-C₁₋₄-alkyl, inparticular dimethylaminomethyl, dimethylaminoethyl,C₃₋₆-cycloalkylamino, in particular pyrrolidino, piperidino ormorpholino, amino, hydroxyl, cyano, C₁₋₄-alkoxy, in particular methoxy,C₁₋₄-alkylcarbonyl, in particular methylcarbonyl, C₁₋₄-alkoxycarbonyl,in particular methoxycarbonyl, halogen, in particular fluorine,chlorine, bromine or iodine, or

[0204]  a radical from the groups G⁴, G⁵, G⁶, G⁷ and G⁸

[0205] in which

[0206] n can denote the numbers 0, 1, 2, 3 or 4,

[0207] R¹⁴ represents hydrogen, straight-chain or branched C₁₋₆-alkyl,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1-methylpentyl, C₃₋₆-cycloalkyl, in particularcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, each of which isoptionally substituted,

[0208] R¹⁵ and R¹⁶ independently of one another represent hydrogen,straight-chain or branched C₁₋₆-alkyl, in particular methyl, ethyl,n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl,1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl,1-methylpentyl, C₁₋₆-alkylcarbonyl, in particular methylcarbonyl,ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl,isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl,1-methylbutylcarbonyl, 2-methylbutylcarbonyl, C₂₋₆-alkenyl, inparticular vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl,2-pentenyl, 3-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl,3-methyl-2-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl,1-ethyl-2-pro-penyl, 2-hexenyl, 1,2-dimethyl-3-butenyl,2,3-dimethyl-2-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl,2-ethyl-2-butenyl, 2-ethyl-3-butenyl, C₂₋₆-alkinyl, in particular2-propinyl, 2-butinyl, 3-butinyl, C₃₋₆-cycloalkyl, in particularcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, each of which isoptionally substituted,

[0209] R¹⁵ and R¹⁶ together with the adjacent N—O-group represent acarbocyclic 5-, 6- or 7-membered ring,

[0210] with the proviso in the case where

[0211] R¹ represents hydrogen and methyl, and

[0212] R⁵ represents hydrogen and

[0213]  represents carboxyl,

[0214] Q represents radicals other than methyl,

[0215] B represents radicals other than —NH₂, and

[0216] with the further proviso in the case where

[0217]  represents carboxyl, and

[0218] G² represents tert-butyloxy, benzyloxy and 4-nitro-benzyloxy,

[0219] B represents radicals other than tert-butyloxy, benzyloxy and4-nitro-benzyloxy,

[0220] and its optical isomers and racemates.

[0221] Particularly preferred compounds are those of the formula (Ia)and their salts

[0222] in which

[0223] R¹ represents hydrogen, straight-chain or branched C₁₋₄-alkyl, inparticular methyl, ethyl, C₃₋₆-cycloalkyl, in particular cyclopropyl,

[0224] R² represents hydrogen, straight-chain or branched C₁₋₄-alkyl inparticular methyl, ethyl, propyl, isopropyl, sec-butyl,

[0225] R³ and R⁴ represent hydrogen,

[0226] R⁵ represents hydrogen, straight-chain or branched C₁₋₄-alkyl, inparticular methyl, ethyl, propyl, isopropyl, sec-butyl,hetaryl-C₁₋₂-alkyl, in particular pyrid-2-yl-methyl, pyrid-3-yl-methyl,pyrid-4-yl-methyl, thien-2-yl-methyl, thien-3-yl-methyl,aryl-C₁₋₂-alkyl, in particular benzyl, each of which can optionally besubstituted by radicals from the series consisting of halogen, inparticular fluorine, chlorine, bromine or iodine, hydroxyl, C₁₋₄-alkyl,in particular methyl, or tert-butyl, C₁₋₄-alkoxy, in particular methoxy,ethoxy or tert-butyloxy, C₁₋₂-alkylenedioxy, in particularmethylenedioxy or ethylenedioxy, nitro, amino, C₁₋₄-alkylamino, inparticular methylamino, C₁₋₄-dialkylamino, in particular dimethylamino,C₃₋₆-cycloalkylamino, in particular pyrrolidino, piperidino,C₃₋₆-cycloalkylthioamino, in particular thiomorpholino anddioxothiomorpholino, C₃₋₆-cycloalkyldiamino, in particularN-methyl-piperazino, and

[0227]  represents carboxyl, —CH═CH—NO₂, —C═CH—CN, —C═N—R⁶ or sulphonyl,

[0228] R⁶ represents C₁₋₄-halogenoalkylcarbonyl, in particulartrifluoromethylcarbonyl, trichloromethylcarbonyl, alkyl-C₁₋₄-sulphonyl,in particular methylsulphonyl, ethylsulphonyl, nitro or cyano, and

[0229] Q represents a radical from the group G² and G³

[0230]  in which

[0231]  can denote carboxyl or sulphonyl,

[0232] Y represents oxygen or —NR⁹,

[0233] R⁸ in the case where Y represents nitrogen denotes a cyclic aminogroup linked via a nitrogen atom, in particular pyrrolidino,2-pyrrolin-1-yl, 1-pyrrolyl, piperidino, 1,4-dihydropyridin-1-yl,1-piperazinyl, 1-homopiperazinyl, morpholino, thiomorpholino,dioxothiomorpholino, each of which can optionally be substituted byradicals from the series consisting of halogen, in particular fluorine,chlorine, bromine or iodine, C₁₋₄-alkyl, in particular methyl,hydoxy-C₁₋₄-alkyl, in particular hydroxymethyl, amino-C₁₋₄-alkyl, inparticular aminomethyl, aminoethyl, C₁₋₄-monoalkylamino-C₁₋₄-alkyl, inparticular methylaminomethyl, methylaminoethyl,C₁₋₄-dialkylamino-C₁₋₄-alkyl, in particular dimethylaminomethyl,dimethylaminoethyl, amino, hydroxyl, C₁₋₄-alkoxy, in particular methoxy,C₁₋₄-alkylcarbonyl, in particular methylcarbonyl, C₁₋₄-alkoxycarbonyl,in particular methoxycarbonyl,

[0234] R⁸ and R⁹ independently of one another represent straight-chainor branched C₁₋₄-alkyl, in particular methyl, ethyl, propyl, isopropyl,sec-butyl, C₂₋₄-alkenyl, in particular vinyl, 2-propenyl,1-methyl-2-propenyl, C₂₋₄-alkinyl, in particular ethinyl, 2-propinyl,C₃₋₆-cycloalkyl, in particular cyclopropyl, hetaryl-C₁₋₂-alkyl, inparticular pyridylmethyl and thiazolylmethyl, each of which canoptionally be substituted by radicals from the series consisting ofhalogen, in particular fluorine, chlorine, bromine or iodine,C₁₋₄-alkyl, in particular methyl, hydoxy-C₁₋₄-alkyl, in particularhydroxymethyl, amino-C₁₋₄-alkyl, in particular aminomethyl, aminoethyl,C₁₋₄-monoalkylamino-C₁₋₄-alkyl, in particular methylaminomethyl,methylaminoethyl, C₁₋₄-dialkylamino-C₁₋₄-alkyl, in particulardimethylaminomethyl, dimethylaminoethyl, amino, hydroxyl, C₁₋₄-alkoxy,in particular methoxy, C₁₋₄-alkylcarbonyl, in particular methylcarbonyl,C₁₋₄-alkoxycarbonyl, in particular methoxycarbonyl, or

[0235] R⁸ and R⁹ together with the adjacent N atom represent acarbocyclic 5-, 6- or 7-membered ring system, which can optionally alsobe interrupted by oxygen, sulphur, sulphoxyl, carbonyl, —N═, —NR¹¹— orby quaternized nitrogen and is optionally substituted by C₁₋₄-alkyl, inparticular methyl, hydoxy-C₁₋₄-alkyl, in particular hydroxymethyl,amino-C₁₋₄-alkyl, in particular aminomethyl, aminoethyl,C₁₋₄-monoalkylamino-C₁₋₄-alkyl, in particular methylaminomethyl,methylaminoethyl, C₁₋₄-dialkylamino-C₁₋₄-alkyl, in particulardimethylaminomethyl, dimethylaminoethyl, amino, hydroxyl, C₁₋₄-alkoxy,in particular methoxy, C₁₋₄-alkylcarbonyl, in particular methylcarbonyl,C₁₋₄-alkoxycarbonyl, in particular methoxycarbonyl, halogen, inparticular fluorine, chlorine, bromine or iodine,

[0236] R¹⁰ represents hydrogen or C₁₋₄-alkyl, in particular methyl, and

[0237] R¹¹ represents hydrogen, straight-chain or branched C₁₋₆-alkyl,in particular methyl, ethyl, C₂₋₆-alkenyl, in particular vinyl,C₃₋₆-cycloalkyl, in particular cyclopropyl, C₁₋₄-alkylcarbonyl, inparticular methylcarbonyl, C₃₋₆-cycloalkylcarbonyl, in particularcyclopropylcarbonyl, C₁₋₄-alkoxycarbonyl, in particular methoxycarbonyl,ethoxycarbonyl, tert-butoxycarbonyl, hydroxy-C₁₋₄-alkyl, in particularhydroxyethyl, hydroxysulphonylethyl, C₁₋₄-alkylamino, in particularethylamino, C₁₋₄-monoalkylamino-C₁₋₄-alkyl, in particularmethylaminoethyl, C₁₋₄-dialkylamino-C₁₋₄-alkyl, in particulardimethylaminoethyl, C₃₋₇-cycloalkylamino-C₁₋₄-alkyl, in particularN-morpholinoethyl, N-piperidinoethyl,C₃₋₆-cycloalkylaminocarbonyl-C₁₋₂-alkyl, in particularN-morpholinocarbonylmethyl, cyano, aryl, in particular phenyl,aryl-C₁₋₂-alkyl, in particular phenylmethyl, hetaryl, in particularpyridyl or thiazolyl, hetaryl-C₁₋₂-alkyl, in particular pyridylmethyland thiazolylmethyl, each of which can optionally be substituted byradicals from the series consisting of halogen, in particular fluorine,chlorine, bromine or iodine, C₁₋₄-alkyl, methyl, C₁₋₄-halogenoalkyl, inparticular trifluoromethyl, trichloromethyl, amino, hydroxyl,C₁₋₄-alkoxy, in particular methoxy, C₁₋₂-alkylenedioxy, in particularmethylenedioxy or ethylenedioxy, C₁₋₄-halogenoalkoxy, in particulartrifluoromethoxy, difluoromethoxy, C₁₋₄-alkylthio, in particularmethylthio, C₁₋₄-halogenoalkylthio, in particular trifluoromethylthio,C₁₋₄-alkylsulphonyl in particular methylsulphonyl, C₁₋₄-alkylamino, inparticular methylamino, di-C₁₋₄-alkylamino, in particular dimethylamino,C₁₋₄-alkylcarbonyl, in particular methylcarbonyl, C₁₋₄-alkoxycarbonyl,in particular methoxycarbonyl,

[0238] B represents straight-chain or branched C₁₋₆-alkoxy, inparticular methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,sec-butoxy and tert-butoxy, C₂₋₆-alkenyloxy, vinyloxy, 2-propenyloxy,1,1-dimethyl-2-propenyloxy, 1,2-dimethyl-2-propenyloxy,1-ethyl-2-propenyloxy, C₂₋₆-alkinyloxy, in particular 2-propinyloxy,1-methyl-2-propinyloxy, 1,1-dimethyl-2-propinyloxy, C₃₋₈-cycloalkyloxy,in particular cyclopropyloxy, cyclohexyloxy,C₃₋₇-cycloalkyl-C₁₋₂-alkyloxy, in particular cyclopropylmethoxy,cyclohexylmethoxy, aryloxy-, in particular phenoxy, aryl-C₁₋₂-alkyloxy,in particular benzyloxy, hetaryloxy, in particular pyridyloxy,hetaryl-C₁₋₂-alkyloxy, in particular pyridylmethyl and thiazolylmehyl,each of which can be optionally substituted by radicals from the seriesconsisting of halogen, in particular fluorine, chlorine, bromine oriodine, hydroxyl, C₁₋₄-alkyl, in particular methyl, C₁₋₄-halogenoalkyl,in particular trifluoromethyl, Trichloromethyl, amino, hydroxyl,C₁₋₄-alkoxy, in particular methoxy, C₁₋₂-alkylenedioxy, in particularmethylenedioxy or ethylenedioxy, C₁₋₄-alkylamino, in particularmethylamino, C₁₋₄-dialkylamino, in particular dimethylamino,C₃₋₆-cycloalkylamino, in particular pyrrolidino, piperidino,C₃₋₆-cycloalkylthioamino, in particular thiomorpholino anddioxothiomorpholino, C₃₋₆-cycloalkyldiamino, in particularN-methylpiperazino, or represents the amino radicals —NR¹²R¹³,—NR¹⁴—NR¹²R¹³ and —NR¹⁵—OR¹⁶,

[0239]  in which

[0240] R¹² and R¹³ independently of one another represent hydrogen,straight-chain or branched C₁₋₆-alkyl, in particular methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,1-methylbutyl, 2,2-dimethylpropyl, C₁₋₆-alkylcarbonyl, in particularmethylcarbonyl, sec-butylcarbonyl, C₁₋₆-alkylsulphonyl, in particularmethylsulphonyl, ethylsulphonyl, C₂₋₆-alkenyl, in particular vinyl,2-propenyl, 1,2-dimethyl-2-propenyl, 2,3-dimethyl-2-butenyl,1-ethyl-2-butenyl, C₂₋₆-alkinyl, in particular 2-propinyl, 2-butinyl,C₃₋₈-cycloalkyl, in particular cyclopropyl, cyclohexyl,C₃₋₈-cycloalkyl-C₁₋₂-alkyl, in particular cyclopropylmethyl,cyclobutylmethyl, hydoxy-C₁₋₄-alkyl, in particular hydroxymethyl,hydroxyethyl, hydroxyethylsulphonylethyl, C₁₋₄-alkylamino, in particularmethylamino, ethylamino, C₁₋₄-monoalkylamino-C₁₋₄-alkyl, in particularmethylaminomethyl, methylaminoethyl, C₁₋₄-dialkylamino-C₁₋₄-alkyl, inparticular dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,C₃₋₇-cycloalkylamino-C₁₋₄-alkyl, in particular N-pyrrolidinoethyl,N-morpholinoethyl, N-piperidinoethyl, N-thiomorpholino-ethyl,N¹-(N⁴-methyl-piperazino)-ethyl,C₃₋₆-cycloalkylaminocarbonyl-C₁₋₂-alkyl, in particularN-morpholinocarbonylmethyl, aryl, in particular phenyl, aryl-C₁₋₂-alkyl,in particular benzyl, hetaryl-C₁₋₆-alkyl, in particular pyridylmethyl,thiazolylmethyl, each of which is optionally substituted by radicalsfrom the series consisting of halogen, in particular fluorine, chlorine,bromine or iodine, hydroxyl, C₁₋₄-alkyl, in particular methyl ortert-butyl, C₁₋₄-alkoxy, in particular methoxy, ethoxy or tert-butyloxy,nitro, amino, C₁₋₄-alkylamino, in particular methylamino,C₁₋₄-dialkylamino, in particular dimethylamino, or

[0241] R¹² and R¹³ together with the adjacent N atom represent acarbocyclic 5-, 6-, 7- or 8-membered ring system which can optionallyalso be interrupted by oxygen, sulphur, sulphonyl, carbonyl, —N═, —NR¹¹—or by quaternized nitrogen and is optionally substituted by C₁₋₄-alkyl,in particular methyl, hydoxy-C₁₋₄-alkyl, in particular hydroxymethyl,amino-C₁₋₄-alkyl, in particular aminomethyl, aminoethyl,C₁₋₄-monoalkylamino-C₁₋₄-alkyl, in particular methylaminomethyl,methylaminoethyl, C₁₋₄-dialkylamino-C₁₋₄-alkyl, in particulardimethylaminoethyl, C₃₋₆-cycloalkylamino, in particular pyrrolidino,piperidino or morpholino, amino, hydroxyl, C₁₋₄-alkoxy, in particularmethoxy, C₁₋₄-alkylcarbonyl, in particular methylcarbonyl,C₁₋₄-alkoxycarbonyl, in particular methoxycarbonyl, or

[0242]  a radical from the groups G⁴, G⁵, G⁶, G⁷ and G⁸

[0243]  in which

[0244] n can denote the numbers 0, 1, 2, or 3,

[0245] R¹⁴ represents hydrogen, straight-chain or branched C₁₋₆-alkyl,in particular methyl, ethyl, sec-butyl, C₃₋₆-cycloalkyl, in particularcyclopropyl,

[0246] R¹⁵ and R¹⁶ independently of one another represent hydrogen,straight-chain or branched C₁₋₆-alkyl, in particular methyl, ethyl,sec-butyl, C₁₋₆-alkylcarbonyl, in particular methylcarbonyl,sec-butylcarbonyl, C₂₋₆-alkenyl, in particular 2-propenyl,1-methyl-2-propenyl, 1,1-dimethyl-2-propenyl, C₂₋₆-alkinyl, inparticular 2-propinyl, C₃₋₆-cycloalkyl, in particular cyclopropyl,

[0247] R¹⁵ and R¹⁶ together with the adjacent N—O-group represent acarbocyclic 5-, 6- or 7-membered ring,

[0248] with the proviso in the case where

[0249] R¹ represents hydrogen and methyl, and

[0250] R⁵ represents hydrogen and

[0251]  represents carboxyl,

[0252] Q represents radicals other than methyl,

[0253] B represents radicals other than —NH₂,and

[0254] with the further proviso in the case where

[0255]  represents carboxyl, and

[0256] G² represents tert-butyloxy, benzyloxy and 4-nitro-benzyloxy,

[0257] B represents radicals other than tert-butyloxy, benzyloxy and4-nitro-benzyloxy,

[0258] and its optical isomers and racemates.

[0259] Very particularly preferred compounds are those of the formula(Ia) and their salts

[0260] in which

[0261] R¹ represents straight-chain or branched C₁₋₄-alkyl, inparticular methyl,

[0262] R² represents straight-chain or branched C₁₋₄-alkyl, inparticular methyl or ethyl,

[0263] R³ and R⁴ represent hydrogen,

[0264] R⁵ represents hydrogen, straight-chain or branched C₁₋₄-alkyl, inparticular methyl or ethyl,

[0265]  represents carboxyl or sulfonyl,

[0266] Q represents a radical from the group G² and G³

[0267]  in which

[0268] can denote carboxyl or sulphonyl,

[0269] Y represents oxygen or —NR⁹,

[0270] R⁸ in the case where Y represents nitrogen, denotes a cyclicamino group linked via a nitrogen atom, in particular pyrrolidino,2-pyrrolin-1-yl, 1-pyrrolyl, piperidino, 1-piperazinyl, morpholino,thiomorpholino, dioxothiomorpholino,

[0271] R⁸ and R⁹ independently of one another represent straight-chainor branched C₁₋₄-alkyl, in particular methyl, ethyl, propyl, isopropyl,sec-butyl, C₂₋₄-alkenyl, in particular vinyl, 2-propenyl,1-methyl-2-propenyl and C₂₋₄-alkinyl, in particular ethinyl, 2-propinyl,C₃₋₆-cycloalkyl, in particular cyclopropyl, hetaryl-C₁₋₂-alkyl, inparticular 2-chloro-pyrid-5-yl-methyl and chloro-thiazol-5-yl-methyl, or

[0272] R⁸ and R⁹ together with the adjacent N atom represent acarbocyclic 5-, 6- or 7-membered ring system which can optionally alsobe interrupted by oxygen, sulphur, sulphonyl, carbonyl, —N═, —NR¹¹— orby quaternized nitrogen and is optionally substituted by C₁₋₄-alkyl, inparticular methyl, C₁₋₄-dialkylamino-C₁₋₄-alkyl, in particulardimethylaminoethyl, hydroxyl, C₁₋₄-alkoxycarbonyl, but particularlypreferably methoxycarbonyl, in particular pyrrolidino, 3-oxopyrrolidino,morpholino, 2,6-dimethylmorpholino, thiomorpholino, dioxothiomorpholino,

[0273] R¹⁰ represents hydrogen or C₁₋₄-alkyl, in particular methyl,

[0274] R¹¹ stands straight-chain or branched C₁₋₆-alkyl, in particularmethyl, C₂₋₆-alkenyl, in particular vinyl, C₃₋₆-cycloalkyl, inparticular cyclopropyl, C₁₋₄-alkylcarbonyl, in particularmethylcarbonyl, C₃₋₆-cycloalkylcarbonyl, in particularcyclopropylcarbonyl, cyclohexylcarbonyl, C₁₋₄-alkoxycarbonyl, inparticular methoxycarbonyl, hydroxy-C₁₋₄-alkyl, in particularhydroxyethyl, hydroxysulphonylethyl, C₁₋₄-alkylamino, in particularethylamino, C₁₋₄-dialkylamino-C₁₋₄-alkyl, in particulardimethylaminoethyl, C₃₋₇-cycloalkylamino-C₁₋₄-alkyl, in particularN-morpholinoethyl, N-piperidinoethyl,C₃₋₆-cycloalkylaminocarbonyl-C₁₋₂-alkyl, in particularN-morpholinocarbonylmethyl,

[0275] B represents straight-chain or branched C₁₋₆-alkoxy, inparticular methoxy, ethoxy, n-propoxy, sec-butoxy and tert-butoxy,C₂₋₆-alkenyloxy, 2-propenyloxy, 1,1-dimethyl-2-propenyloxy,C₂₋₆-alkinyloxy, in particular 2-propinyloxy, 1-methyl-2-propinyloxy,C₃₋₈-cycloalkyloxy, in particular cyclopropyloxy, aryl-C₁₋₂-alkyloxy, inparticular benzyloxy, hetaryloxy, in particular pyridyloxy,hetaryl-C₁₋₂-alkyloxy, in particular pyridylmethyloxy andthiazolylmethyloxy, each of which can optionally be substituted byradicals from the series consisting of halogen, in particular fluorine,chlorine, bromine or iodine, amino, hydroxyl, C₁₋₄-alkoxy, in particularmethoxy, C₁₋₄-alkylamino, in particular methylamino, C₁₋₄-dialkylamino,in particular dimethylamino, C₃₋₆-cycloalkylamino, in particularpiperidino, C₃₋₆-cycloalkylthioamino, in particular dioxothiomorpholino,C₃₋₆-cycloalkyldiamino, in particular N-methyl-piperazino, or representsthe amino radicals —NR¹²R¹³, —NR¹⁴—NR¹²R¹³ and —NR¹⁵—OR¹⁶,

[0276]  in which

[0277] R¹² and R¹³ independently of one another represent hydrogen,straight-chain or branched C₁₋₆-alkyl, in particular methyl, ethyl,C₁₋₆-alkylcarbonyl, in particular methylcarbonyl, C₁₋₆-alkylsulphonyl,in particular methylsulphonyl, C₂₋₆-alkenyl, in particular 2-propenyl,1-methyl-2-propenyl, C₂₋₆-alkinyl, in particular 2-propinyl,C₃₋₈-cycloalkyl, in particular cyclopropyl, cyclohexyl,C₃₋₈-cycloalkyl-C₁₋₂-alkyl, in particular cyclopropylmethyl,hydoxy-C₁₋₄-alkyl, in particular hydroxymethyl,hydroxyethylsulphonylethyl, C₁₋₄-dialkylamino-C₁₋₄-alkyl, in particulardimethylaminoethyl, C₃₋₇-cycloalkylamino-C₁₋₄-alkyl, in particularN-morpholinoethyl, N¹-(N⁴-methyl-piperazino)-ethyl,C₃₋₆-cycloalkylaminocarbonyl-C₁₋₂-alkyl, in particularN-morpholinocarbonylmethyl, or

[0278] R¹² and R¹³ together with the adjacent N atom represent acarbocyclic 5-, 6-, 7- or 8-membered ring system which can optionallyalso be interrupted by oxygen, sulphur, carbonyl, —N═, —NR¹¹— byquaternized nitrogen and is optionally substituted by C₁₋₄-alkyl, inparticular methyl, C₁₋₄-dialkylamino-C₁₋₄-alkyl, in particulardimethylaminoethyl, C₃₋₆-cycloalkylamino, in particular piperidino,hydroxyl, C₁₋₄-alkoxy, in particular methoxy, C₁₋₄-alkylcarbonyl inparticular methylcarbonyl, C₁₋₄-alkoxycarbonyl, in particularmethoxycarbonyl, or

[0279]  a radical from the groups G⁴, G⁵, G⁶, G⁷ and G⁸

[0280]  in which

[0281] n can denote the numbers 0, 1 or 2,

[0282] R¹⁴ represents hydrogen, straight-chain or branched C₁₋₆-alkyl,in particular methyl,

[0283] R¹⁵ and R¹⁶ independently of one another represents hydrogen,straight-chain or branched C₁₋₆-alkyl, in particular methyl,C₁₋₆-alkylcarbonyl, in particular methylcarbonyl, sec-butylcarbonyl,C₂₋₆-alkenyl, in particular 2-propenyl, C₂₋₆-alkinyl, in particular2-propinyl, C₃₋₆-cycloalkyl, in particular cyclopropyl,

[0284] with the proviso in the case where

[0285] R¹ represents hydrogen and methyl, and

[0286] R⁵ represents hydrogen and

[0287]  represents carboxyl,

[0288] Q represents radicals other than methyl,

[0289] B represents radicals other than —NH₂, and

[0290] with the further proviso in the case where

[0291]  represents carboxyl, and

[0292] G² represents tert-butyloxy, benzyloxy and 4-nitro-benzyloxy,

[0293] B represents radicals other than tert-butyloxy, benzyloxy and4-nitro-benzyloxy,

[0294] and its optical isomers and racemates.

[0295] The compound of the general formula (I) to be used according tothe invention and their salts additionally contain one or more centresof chirality and can thus be present in pure stereoisomers or in theform of various enantiomer and diastereomer mixtures which, ifnecessary, can be separated in a manner known per se. The inventiontherefore relates both to the pure enantiomers and diastereomers, and totheir mixtures for the control of endoparasites, particularly in thefield of medicine and veterinary medicine.

[0296] Preferably, however, the optically active, stereoisomeric formsof the compounds of the general formula (I) and their salts are usedaccording to the invention.

[0297] Suitable salts of the compounds of the general formula (I) whichcan be mentioned are customary non-toxic salts, i.e. salts with variousbases and salts with added acids. Preferably, salts with inorganic,bases such as alkali metal salts, for example sodium, potassium orcaesium salts, alkaline earth metal salts, for example calcium ormagnesium salts, ammonium salts, salts with organic bases and also withorganic amines, for example triethylammonium, pyridinium, picolinium,ethanolammonium, triethanolammonium, dicyclohexylammonium orN,N′-dibenzylethylenediammonium salts, salts with inorganic acids, forexample hydrochlorides, hydrobromides, dihydrosulphates ortrihydrophosphates, salts with organic carboxylic acids or organicsulpho acids, for example formates, acetates, trifluoroacetates,maleates, tartrates, methanesulphonates, benzenesulphonates orpara-toluenesulphonates, salts with basic amino acids or acidic aminoacids, for example arginates, aspartates or glutamates, may bementioned.

[0298] In particular, the groups of compounds mentioned in the followingTables 1 to 84 may be mentioned.

[0299] Very particularly preferred compounds are those of the formula(Ia-1) and their salts, consisting of the N-methyl-amino acidN-methyl-alanine (R¹, R²=methyl and R³=hydrogen) and the2-hydroxycarboxylic acid 2-hydroxyacetic acid (R⁴, R⁵=hydrogen) whichare indicated in the following Tables 1 to 13. TABLE 1 (Ia-1)

Compounds of the Table 1 correspond to the general formula (Ia-1) inwhich

represents carboxyl; Q = —NMe₂, B = as listed in the following: CompoundNo. B 1 —O—Me 2 —O—CH₂—Me 3 —O—(CH₂)₂—Me 4 —O—CHMe₂ 5 —O—CMe₃ 6—O—CHMe—CH₂—Me 7 —O—CH₂—CH═CH₂ 8 —O—CHMe—CH═CH₂ 9 —O—CMe₂—CH═CH₂ 10—O—CH₂—C≡CH 11 —O—CHMe—C≡CH 12 —NMe₂ 13 —NMe—(CH₂)₂—Me 14 —NH—Me 15—O—Cyclopropyl 16

17

18

19 —NMe—(CH₂)₃—Me 20 —NMe—CHMe—CH₂—Me 21 —NMe—(CH₂)₂—NMe₂ 22—NMe—(CH₂)₃—NMe₂ 23 —NMe—CH₂—CH═CH₂ 24 —NMe—CH₂—C≡CH 25 —N(CH₂—CH₂—OH)₂26 —N[(CH₂)₂—SO₂—(CH₂)₂—OH]₂ 27 —NMe(CH₂)₂—SO₂—(CH₂)₂—OH 28—NMe—CO—CH₂—O—CH₂—COOH 29 —NMe—O—Me 30 —N(CH₂—Me)₂ 31 —NMe—CH₂—Me 32—NEt—(CH₂)₂—Me 33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

 47a

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

[0300] TABLE 2 Table 2 contains the compounds of the general formula(Ia-1) in which

represents carboxyl; Q represents —NEt₂ and B has the meanings listed inTable 1.

[0301] TABLE 3 Table 3 contains the compounds of the general formula(Ia-1) in which

represents carboxyl; Q represents —O—Me and B has the meanings listed inTable 1.

[0302] TABLE 4 Table 4 contains the compounds of the general formula(Ia-1) in which

represents carboxyl; Q represents —O—CHMe—CH₂—Me and B has the meaningslisted in Table 1.

[0303] TABLE 5 Table 5 contains the compounds of the general formula(Ia-1) in which

represents carboxyl; Q represents —O—CH₂—CH═CH₂ and B has the meaningslisted in Table 1.

[0304] TABLE 6 Table 6 contains the compounds of the general formula(Ia-1) in which

represents carboxyl; Q represents —O—CHMe—CH═CH₂ and B has the meaningslisted in Table 1.

[0305] TABLE 7 Table 7 contains the compounds of the general formula(Ia-1) in which

represents carboxyl; Q represents —O—CH₂—C≡CH and B has the meaningslisted in Table 1.

[0306] TABLE 8 Table 8 contains the compounds of the general formula(Ia-1) in which

represents carboxyl; Q represents —O—CMe═CH₂ and B has the meaningslisted in Table 1.

[0307] TABLE 9 Table 9 contains the compounds of the general formula(Ia-I) in which

represents carboxyl; Q represents —NMe—CO—NMe₂ and B has the meaningslisted in Table 1.

[0308] TABLE 10 Table 10 contains the compounds of the general formula(Ia-1) in which

represents carboxyl; Q represents —NMe—CO—NEt₂ and B has the meaningslisted in Table 1.

[0309] TABLE 11

[0310] TABLE 12

[0311] TABLE 13

[0312] TABLE 14

[0313] Furthermore preferred are the compounds of the formula (Ia-2) andtheir salts, consisting of the N-methyl-amino acid N-methyl-alanine (R¹,R²=methyl and R³=hydrogen) and the 2-hydroxycarboxylic acid2-hydroxy-propionic acid (lactic acid) R⁴=hydrogen; R⁵=methyl).

[0314] Very particularly preferred examples of these new compounds(Ia-2) according to the invention are mentioned in Tables 15-28. TABLE15 (Ia-2)

[0315] TABLE 16

[0316] TABLE 17

[0317] TABLE 18

[0318] TABLE 19

[0319] TABLE 20

[0320] TABLE 21 Table 21 contains the compounds of the general formula(Ia-2) in which

represents carboxyl; Q represents —O—CH₂—C≡CH and B has the meaningslisted in Table 1.

[0321] TABLE 22 Table 22 contains the compounds of the general formula(Ia-2) in which

represents carboxyl; Q represents —O—CMe═CH₂ and B has the meaningslisted in Table 1.

[0322] TABLE 23 Table 23 contains the compounds of the general formula(Ia-2) in which

represents carboxyl; Q represents —NMe—CO—NMe₂ and B has the meaningslisted in Table 1.

[0323] TABLE 24 Table 24 contains the compounds of the general formula(Ia-2) in which

represents carboxyl; Q represents —NMe—CO—NEt₂ and B has the meaningslisted in Table 1.

[0324] TABLE 25 Table 25 contains the compounds of the general formula(Ia-2) in which

represents carboxyl; Q represents

and B has the meanings listed in Table 1.

[0325] TABLE 26 Table 26 contains the compounds of the general formula(Ia-2) in which

represents sulphonyl; Q represents —NMe₂ and B has the meanings listedin Table 1.

[0326] TABLE 27 Table 27 contains the compounds of the general formula(Ia-2) in which

represents sulphonyl; Q represents —NEt₂ and B has the meanings listedin Table 1.

[0327] TABLE 28 Table 28 contains the compounds of the general formula(Ia-2) in which

represents sulphonyl; Q represents

and B has the meanings listed in Table 1.

[0328] Furthermore preferred are the compounds of the formula (Ia-3) andtheir salts, consisting of the N-methyl-amino acid N-methyl-alanine (R¹,R²=methyl and R³=hydrogen) and the 2-hydroxycarboxylic acid2-hydroxy-butyric acid (R⁴=hydrogen; R⁵=ethyl).

[0329] Very particuarly preferred examples of these new compounds (Ia-3)according to the invention are mentioned in Tables 29-42. TABLE 29(Ia-3)

Compounds of Table 29 correspond to the general formula (Ia-3) in which

represents carboxyl; Q represents —NMe₂ and B has the meanings listed inTable 1.

[0330] TABLE 30 Table 30 contains the compounds of the general formula(Ia-3) in which

represents carboxyl; Q represents —NEt₂ and B has the meanings listed inTable 1.

[0331] TABLE 31 Table 31 contains the compounds of the general formula(Ia-3) in which

represents carboxyl; Q represents —O—Me and B has the meanings listed inTable 1.

[0332] TABLE 32 Table 32 contains the compounds of the general formula(Ia-3) in which

represents carboxyl; Q represents —O—CHMe—CH₂—Me and B has the meaningslisted in Table 1.

[0333] TABLE 33 Table 33 contains the compounds of the general formula(Ia-3) in which

represents carboxyl; Q represents —O—CH₂—CH═CH₂ and B has the meaningslisted in Table 1.

[0334] TABLE 34 Table 34 contains the compounds of the general formula(Ia-3) in which

represents carboxyl; Q represents —O—CHMe—CH═CH_(2 and) B has themeanings listed in Table 1.

[0335] TABLE 35 Table 35 contains the compounds of the general formula(Ia-3) in which

represents carboxyl; Q represents —O—CH₂C≡CH and B has the meaningslisted in Table 1.

[0336] TABLE 36 Table 36 contains the compounds of the general formula(Ia-3) in which

represents carboxyl; Q represents —O—CMe═CH₂ and B has the meaningslisted in Table 1.

[0337] TABLE 37 Table 37 contains the compounds of the general formula(Ia-3) in which

represents carboxyl; Q represents —NMe—CO—NMe₂ and B has the meaningslisted in Table 1.

[0338] TABLE 38 Table 38 contains the compounds of the general formula(Ia-3) in which

represents carboxyl; Q represents —NMe—CO—NEt₂ and B has the meaningslisted in Table 1.

[0339] TABLE 39 Table 39 contains the compounds of the general formula(Ia-3) in which

represents carboxyl; Q represents

and B has the meanings listed in Table 1.

[0340] TABLE 40 Table 40 contains the compounds of the general formula(Ia-3) in which

represents sulphonyl; Q represents —NMe₂ and B has the meanings listedin Table 1.

[0341] TABLE 41 Table 41 contains the compounds of the general formula(Ia-3) in which

represents sulphonyl; Q represents —NEt₂ and B has the meanings listedin Table 1.

[0342] TABLE 42 Table 42 contains the compounds of the general formula(Ia-3) in which

represents sulphonyl; Q represents

and B has the meanings listed in Table 1.

[0343] Furthermore preferred are the compounds of the formula (Ia-4) andtheir salts, consisting of the N-methyl-amino acid N-methyl-aminobutyricacid (R¹=methyl, R²=ethyl and R³=hydrogen) and the 2-hydroxycarboxylicacid 2-hydroxyacetic acid (R⁴, R⁵=hydrogen).

[0344] Very particularly preferred examples of these new compounds(Ia-4) according to the invention are mentioned in Tables 43-56. TABLE43 (Ia-4)

Compounds of Table 43 correspond to the general formula (Ia-4) in which

represents carboxyl; Q represents —NMe₂ and B has the meanings listed inTable 1.

[0345] TABLE 44 Table 44 contains the compounds of the general formula(Ia-4) in which

represents carboxyl; Q represents —NEt₂ and B has the meanings listed inTable 1.

[0346] TABLE 45 Table 45 contains the compounds of the general formula(Ia-4) in which

represents carboxyl; Q represents —O—Me and B has the meanings listed inTable 1.

[0347] TABLE 46 Table 46 contains the compounds of the general formula(Ia-4) in which

represents carboxyl; Q represents —O—CHMe—CH₂—Me and B has the meaningslisted in Table 1.

[0348] TABLE 47 Table 47 contains the compounds of the general formula(Ia-4) in which

represents carboxyl; Q represents —O—CH₂—CH═CH₂ and B has the meaningslisted in Table 1.

[0349] TABLE 48 Table 48 contains the compounds of the general formula(Ia-4) in which

represents carboxyl; Q represents —O—CHMe—CH═CH₂ and B has the meaningslisted in Table 1.

[0350] TABLE 49 Table 49 contains the compounds of the general formula(Ia-4) in which

represents carboxyl; Q represents —O—CH₂—C≡CH and B has the meaningslisted in Table 1.

[0351] TABLE 50 Table 50 contains the compounds of the general formula(Ia-4) in which

represents carboxyl; Q represents —O—CMe═CH₂ and B has the meaningslisted in Table 1.

[0352] TABLE 51

[0353] TABLE 52

[0354] TABLE 53

[0355] TABLE 54

[0356] TABLE 55

[0357] TABLE 56

[0358] Furthermore preferred are the compounds of the formula (Ia-5) andtheir salts, consisting of the N-methyl-amino acid N-methyl-aminobutyricacid (R¹=methyl, R²=ethyl and R³=hydrogen) and the 2-hydroxycarboxylicacid 2-hydroxypropionic acid (lactic acid) (R⁴=hydrogen; R⁵=methyl).

[0359] Very particularly preferred examples of these new compounds(Ia-5) acccording to the invention are mentioned in Tables 57-70. TABLE57 (Ia-5)

[0360] TABLE 58

[0361] TABLE 59

[0362] TABLE 60

[0363] TABLE 61 Table 61 contains the compounds of the general formula(Ia-5) in which

represents carboxyl; Q represents —O—CH₂—CH═CH₂ and B has the meaningslisted in Table 1.

[0364] TABLE 62 Table 62 contains the compounds of the general formula(Ia-5) in which

represents carboxyl; Q represents —O—CHMe—CH═CH₂ and B has the meaningslisted in Table 1.

[0365] TABLE 63 Table 63 contains the compounds of the general formula(Ia-5) in which

represents carboxyl; Q represents —O—CH₂—C≡CH and B has the meaningslisted in Table 1.

[0366] TABLE 64 Table 64 contains the compounds of the general formula(Ia-5) in which

represents carboxyl; Q represents —O—CMe═CH₂ and B has the meaningslisted in Table 1.

[0367] TABLE 65 Table 65 contains the compounds of the general formula(Ia-5) in which

represents carboxyl; Q represents —NMe—CO—NMe₂ and B has the meaningslisted in Table 1.

[0368] TABLE 66 Table 66 contains the compounds of the general formula(Ia-5) in which

represents carboxyl; Q represents —NMe—CO—NEt₂ and B has the meaningslisted in Table 1.

[0369] TABLE 67 Table 67 contains the compounds of the general formula(Ia-5) in which

represents carboxyl; Q represents

and B has the meanings listed in Table 1.

[0370] TABLE 68 Table 68 contains the compounds of the general formula(Ia-5) in which

represents sulphonyl; Q represents —NMe₂ and B has the meanings listedin Table 1.

[0371] TABLE 69 Table 69 contains the compounds of the general formula(Ia-5) in which

represents sulphonyl; Q represents —NEt₂ and B has the meanings listedin Table 1.

[0372] TABLE 70 Table 70 contains the compounds of the general formula(Ia-5) in which

represents sulphonyl; Q represents

and B [lacuna] the [lacuna] in Table 1 listed.

[0373] Furthermore preferred are the compounds of the formula (Ia-6) andtheir salts, consisting of the N-methyl-amino acid N-methyl-aminobutyricacid (R¹=methyl, R²=ethyl and R³=hydrogen) and the 2-hydroxycarboxylicacid 2-hydroxybutyric acid (R⁴=hydrogen; R⁵=ethyl).

[0374] Very particularly preferred examples of these new compounds(Ia-6) according to the invention are mentioned in Tables 71-84. TABLE71 (Ia-6)

Compounds of Table 71 correspond to the general formula (Ia-6) in which

represents carboxyl; Q represents —NMe₂ and B has the meanings listed inTable 1.

[0375] TABLE 72 Table 72 contains the compounds of the general formula(Ia-6) in which

represents carboxyl; Q represents —NEt₂ and B has the meanings listed inTable 1.

[0376] TABLE 73 Table 73 contains the compounds of the general formula(Ia-6) in which

represents carboxyl; Q represents —O—Me and B has the meanings listed inTable 1.

[0377] TABLE 74 Table 74 contains the compounds of the general formula(Ia-6) in which

represents carboxyl; Q represents —O—CHMe—CH₂—Me and B has the meaningslisted in Table 1.

[0378] TABLE 75 Table 75 contains the compounds of the general formula(Ia-6) in which

represents carboxyl; Q represents —O—CH₂—CH═CH₂ and B has the meaningslisted in Table 1.

[0379] TABLE 76 Table 76 contains the compounds of the general formula(Ia-6) in which

represents carboxyl; Q represents —O—CHMe—CH═CH₂ and B has the meaningslisted in Table 1.

[0380] TABLE 77 Table 77 contains the compounds of the general formula(Ia-6) in which

represents carboxyl; Q represents —O—CH₂—C≡CH and B has the meaningslisted in Table 1.

[0381] TABLE 78 Table 78 contains the compounds of the general formula(Ia-6) in which

represents carboxyl; Q represents —O—CMe═CH₂ and B has the meaningslisted in Table 1.

[0382] TABLE 79 Table 79 contains the compounds of the general formula(Ia-6) in which

represents carboxyl; Q represents —NMe—CO—NMe₂ and B has the meaningslisted in Table 1.

[0383] TABLE 80 Table 80 contains the compounds of the general formula(Ia-6) in which

represents carboxyl; Q represents —NMe—CO—NEt₂ and B has the meaningslisted in Table 1.

[0384] TABLE 81 Table 81 contains the compounds of the general formula(Ia-6) in which

represents carboxyl, Q represents

and B has the meanings listed in Table 1.

[0385] TABLE 82 Table 82 contains the compounds of the general formula(Ia-6) in which

represents sulphonyl; Q represents —NMe₂ and B has the meanings listedin Table 1.

[0386] TABLE 83 Table 83 contains the compounds of the general formula(Ia-6) in which

represents sulphonyl; Q represents —NEt₂ and B has the meanings listedin Table 1.

[0387] TABLE 84 Table 84 contains the compounds of the general formula(Ia-6) in which

represents sulphonyl; Q represents

and B has the meanings listed in Table 1.

[0388] In detail, the following compounds of the general formula (Ia)may be mentioned in which the radicals R¹ to R⁵, G, Q, X and B have thefollowing meaning:

Q G═X R¹ R² R³ R⁴ R⁵ B Me₂N—CO—NMe- C═O -Me -Me —H —H -Me

Et₂N—CO—NMe- C═O -Me -Me —H —H -Me

Me-CH₂-MeCH—O— C═O -Me -Me —H —H -Me

H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me

H₂C═CMe-O— C═O -Me -Me —H —H -Me

HC≡C—CH₂—O— C═O -Me -Me —H —H -Me

Et₂N— SO₂ -Me -Me —H —H -Me

Me₂N— C═O -Me -Me —H —H -Me

Me₂N— SO₂ -Me -Me —H —H -Me

Et₂N— C═O -Me -Me —H —H -Me

SO₂ -Me -Me —H —H -Me

SO₂ -Me -Me —H —H -Me

SO₂ -Me -Me —H —H -Me

C═O -Me -Me —H —H -Me

C═O -Me -Me —H —H -Me

C═O -Me -Me —H —H -Me

-Me -Me —H —H -Me

-Me -Me —H —H -Me

-Me -Me —H —H -Me

Me₂N—CO—NMe- C═O -Me -Me —H —H -Me

Et₂N—CO—NMe- C═O -Me -Me —H —H -Me

Me-CH₂-MeCH—O— C═O -Me -Me —H —H -Me

H₂C═CH—CH₂—O— C═O -Me -Me —H —H -Me

H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me

H₂C═CMe-O— C═O -Me -Me —H —H -Me

HC≡C—CH₂—O— C═O -Me -Me —H —H -Me

Et₂N— SO₂ -Me -Me —H —H -Me

Me₂N— C═O -Me -Me —H —H -Me

Me₂N— SO₂ -Me -Me —H —H -Me

Et₂N— C═O -Me -Me —H —H -Me

SO₂ -Me -Me —H —H -Me

SO₂ -Me -Me —H —H -Me

SO₂ -Me -Me —H —H -Me

C═O -Me -Me —H —H -Me

C═O -Me -Me —H —H -Me

C═O -Me -Me —H —H -Me

-Me -Me —H —H -Me

-Me -Me —H —H -Me

-Me -Me —H —H -Me

Me₂N—CO—NMe- C═O -Me -Me —H —H -Me

Me-CH₂-MeCH—O— C═O -Me -Me —H —H -Me

H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me

H₂C═CMe-O— C═O -Me -Me —H —H -Me

HC≡C—CH₂—O— C═O -Me -Me —H —H -Me

Me₂N— C═O -Me -Me —H —H -Me

Et₂N— C═O -Me -Me —H —H -Me

SO₂ -Me -Me —H —H -Me

SO₂ -Me -Me —H —H -Me

C═O -Me -Me —H —H -Me

C═O -Me -Me —H —H -Me

-Me -Me —H —H -Me

-Me -Me —H —H -Me

-Me -Me —H —H -Me

Me₂N—CO—NMe- C═O -Me -Me —H —H -Me

Me-CH₂-MeCH—O— C═O -Me -Me —H —H -Me

H₂C═CH—CH₂—O— C═O -Me -Me —H —H -Me

H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me

H₂C═CMe-O— C═O -Me -Me —H —H -Me

HC≡C—CH₂—O— C═O -Me -Me —H —H -Me

Me₂N— C═O -Me -Me —H —H -Me

Et₂N— C═O -Me -Me —H —H -Me

SO₂ -Me -Me —H —H -Me

SO₂ -Me -Me —H —H -Me

-Me -Me —H —H -Me

-Me -Me —H —H -Me

-Me -Me —H —H -Me

C═O -Me -Me —H —H -Me

C═O -Me -Me —H —H -Me

Me₂N—CO—NMe C═O -Me -Me —H —H -Me —O-Et Me-CH₂—MeCH—O— C═O -Me -Me —H —H-Me —O-Et H₂C═CH—CH₂—O— C═O -Me -Me —H —H -Me —O-Et H₂C═CH—CHMe-O— C═O-Me -Me —H —H -Me —O-Et H₂C═CMe-O— C═O -Me -Me —H —H -Me —O-EtHC≡C—CH₂—O— C═O -Me _me —H —H -Me —O-Et Me₂N— C═O -Me -Me —H —H -Me—O-Et Et₂N— C═O -Me -Me —H —H -Me —O-Et

SO₂ -Me -Me —H —H -Me —O-Et

SO₂ -Me -Me —H —H -Me —O-Et

-Me -Me —H —H -Me —O-Et

-Me -Me —H —H -Me —O-Et

-Me -Me —H —H -Me —O-Et

C═O -Me -Me —H —H -Me —O-Et

C═O -Me -Me —H —H -Me —O-Et Me₂N—CO—NMe C═O -Me -Me —H —H -Me —NMe₂Me-CH₂MeCH—O— C═O -Me -Me —H —H -Me —NMe₂ H₂C═CH—CH₂—O— C═O -Me -Me —H—H -Me —NMe₂ H₂NC═CH—CHMe-O— C═O -Me -Me —H —H -Me —NMe₂ H₂C═CMe-O— C═O-Me -Me —H —H -Me —NMe₂ HC≡C—CH₂—O— C═O -Me -Me —H —H -Me —NMe₂ Me₂N—C═O -Me -Me —H —H -Me —NMe₂ Et₂N— C═O -Me -Me —H —H -Me —NMe₂

SO₂ -Me -Me —H —H -Me —NMe₂

SO₂ -Me -Me —H —H -Me —NMe₂

-Me -Me —H —H -Me —NMe₂

-Me -Me —H —H -Me —NMe₂

-Me -Me —H —H -Me —NMe₂

C═O -Me -Me —H —H -Me —NMe₂

C═O -Me -Me —H —H -Me —NMe₂ Me₂N—CO—NMe- C═O -Me -Me —H —H -Me —NEt₂Me-CH₂-MeCH—O— C═O -Me -Me —H —H -Me —NEt₂ H₂C═CH—CH₂—O— C═O -Me -Me —H—H -Me —NEt₂ H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me —NEt₂ H₂C═CMe-O— C═O-Me -Me —H —H -Me —NEt₂ HC≡C—CH₂—O— C═O -Me -Me —H —H -Me —NEt₂ Me₂N C═O-Me -Me —H —H -Me —NEt₂ Et₂N— C═O -Me -Me —H —H -Me —NEt₂

-Me -Me —H —H -Me —NEt₂

C═O -Me -Me —H —H -Me —NEt₂ Me₂N—CO—NMe- C═O -Me -Me —H —H -Me

Me-CH₂-MeCH—O— C═O -Me -Me —H —H -Me

H₂C═CH—CH₂—O— C═O -Me -Me —H —H -Me

H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me

H₂C═CMe-O— C═O -Me -Me —H —H -Me

HC≡C—CH₂—O— C═O -Me -Me —H —H -Me

Me₂N— C═O -Me -Me —H —H -Me

Et₂N— C═O -Me -Me —H —H -Me

SO₂ -Me -Me —H —H -Me

SO₂ -Me -Me —H —H -Me

-Me -Me —H —H -Me

-Me -Me —H —H -Me

-Me -Me —H —H -Me

C═O -Me -Me —H —H -Me

C═O -Me -Me —H —H -Me

Me₂N—CO—NMe- C═O -Me -Me —H —H -Me

Me-CH₂-MeCH—O— C═O -Me -Me —H —H -Me

H₂C═CHMe-O— C═O -Me -Me —H —H -Me

H₂C═CMe-O— C═O -Me -Me —H —H -Me

HC≡C—CH₂—O— C═O -Me -Me —H —H -Me

Me₂N— C═O -Me -Me —H —H -Me

Et₂N— C═O -Me -Me —H —H -Me

SO₂ -Me -Me —H —H -Me

SO₂ -Me -Me —H —H -Me

Me₂N—CO—NMe- C═O -Me -Me —H —H -Me

Me-CH₂—MeCH—O— C═O -Me -Me —H —H -Me

H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me

Me₂N—CO—NMe- C═O -Me -Me —H —H -Me —NMe-(CH₂)₂—NMe₂ Me-CH₂-Me-CH—O— C═O-Me -Me —H —H -Me —NMe-(CH₂)₂—NMe₂ H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me—NMe-(CH₂)₂—NMe₂ H₂C═CMe-O— C═O -Me -Me —H —H -Me —NMe-(CH₂)₂—NMe₂HC≡C—CH₂—O— C═O -Me -Me —H —H -Me —NMe-(CH₂)₂—NMe₂ Me₂N— C═O -Me -Me —H—H -Me —NMe-(CH₂)₂—NMe₂ Et₂N— C═O -Me -Me —H —H -Me —NMe-(CH₂)₂—NMe₂

-Me -Me —H —H -Me —NMe-(CH₂)₂—NMe₂

C═O -Me -Me —H —H -Me —NMe-(CH₂)₂—NMe₂ H₂C═CH—CH₂—O— C═O -Me -Me —H —H-Me —NMe-CHMe-CH₂-Me H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me—NMe-CHMe-CH₂-Me H₂C═CMe-O— C═O -Me -Me —H —H -Me —NMe-CHMe-CH₂-MeHC≡C—CH₂—O— C═O -Me -Me —H —H -Me —NMe-CHMe-CH₂-Me Me₂N— C═O -Me -Me —H—H -Me —NMe-CHMe-CH₂-Me Et₂N— C═O -Me -Me —H —H -Me —NMe-CHMe-CH₂-Me

-Me -Me —H —H -Me —NMe-CHMe-CH₂-Me

C═O -Me -Me —H —H -Me —NMe-CHMe-CH₂-Me H₂C═CH—CHMe-O— C═O -Me -Me —H —H-Me —NMe-O-Me H₂C═CMe-O— C═O -Me -Me —H —H -Me —NMe-O-Me HC≡C—CH₂—O— C═O-Me -Me —H —H -Me —NMe-O-Me Me₂N— C═O -Me -Me —H —H -Me —NMe-O-Me Et₂N—C═O -Me -Me —H —H -Me —NMe-O-Me

-Me -Me —H —H -Me —NMe-O-Me

C═O -Me -Me —H —H -Me —NMe-O-Me H₂C═CH—CH₂—O— C═O -Me -Me —H —H -Me—O—Pr H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me —O—Pr H₂C═CMe-O— C═O -Me -Me—H —H -Me —O—Pr HC≡C—CH₂—O— C═O -Me -Me —H —H -Me —O—Pr Me₂N— C═O -Me-Me —H —H -Me —O—Pr Et₂N— C═O -Me -Me —H —H -Me —O—Pr Me₂N—CO—NMe- C═O-Me -Me —H —H -Me —NMe-nPr Me-CH₂-Me-CH—O— C═O -Me -Me —H —H -Me—NMe-nPr H₂C═CH—CH₂—O— C═O -Me -Me —H —H -Me —NMe-nPr H₂C═CH—CHMe-O— C═O-Me -Me —H —H -Me —NMe-nPr H₂C═CMe-O— C═O -Me -Me —H —H -Me —NMe-nPrHC≡C—CH₂—O— C═O -Me -Me —H —H -Me —NMe-nPr Me₂N— C═O -Me -Me —H —H -Me—NMe-nPr Et₂N— C═O -Me -Me —H —H -Me —NMe-nPr

-Me -Me —H —H -Me —NMe-nPr

C═O -Me -Me —H —H -Me —NMe-nPr Me₂N—CO—NMe- C═O -Me -Me —H —H -Me—NMe—CH₂C≡CH Me-CH₂-MeCH—O— C═O -Me -Me —H —H -Me —NMe—CH₂C≡CHH₂C═CH—CH₂—O— C═O -Me -Me —H —H -Me —NMe—CH₂C≡CH H₂C═CH—CHMe-O— C═O -Me-Me —H —H -Me —NMe—CH₂C≡CH H₂C═CMe-O— C═O -Me -Me —H —H -Me —NMe—CH₂C≡CHHC≡C—CH₂—O— C═O -Me -Me —H —H -Me —NMe—CH₂C≡CH Me₂N— C═O -Me -Me —H —H-Me —NMe—CH₂C≡CH Et₂N— C═O -Me -Me —H —H -Me —NMe—CH₂C≡CH

-Me -Me —H —H -Me —NMe—CH₂C≡CH

C═O -Me -Me —H —H -Me —NEt-nPr Me₂N—CO—NMe- C═O -Me -Me —H —H -Me—NMe-(CH₂)₂—SO₂— (CH₂)₂—OH Me-CH₂-Me-CH—O— C═O -Me -Me —H —H -Me—NMe-(CH₂)₂—SO₂— (CH₂)₂—OH H₂C═CH—CH₂—O— C═O -Me -Me —H —H -Me—NMe-(CH₂)₂—SO₂— (CH₂)₂—OH H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me—NMe-(CH₂)₂—SO₂— (CH₂)₂—OH H₂C═CMe-O— C═O -Me -Me —H —H -Me—NMe-(CH₂)₂—SO₂— (CH₂)₂—OH HC≡C—CH₂—O— C═O -Me -Me —H —H -Me—NMe-(CH₂)₂—SO₂— (CH₂)₂—OH Me₂N— C═O -Me -Me —H —H -Me —NMe-(CH₂)₂—SO₂—(CH₂)₂—OH Et₂N— C═O -Me -Me —H —H -Me —NMe-(CH₂)₂—SO₂— (CH₂)₂—OH

-Me -Me —H —H -Me —NMe-(CH₂)₂—SO₂— (CH₂)₂—OH

C═O -Me -Me —H —H -Me —NMe-(CH₂)₂—SO₂— (CH₂)₂—OH Me₂N—CO—NMe- C═O -Me-Me —H —H -Me —N(CH₂—CH₂—OH)₂ Me-CH₂-Me-CH—O— C═O -Me -Me —H —H -Me—N(CH₂—CH₂—OH)₂ H₂C═CH—CH₂—O— C═O -Me -Me —H —H -Me —N(CH₂—CH₂—OH)₂H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me —N(CH₂—CH₂—OH)₂ H₂C═CMe-O— C═O -Me-Me —H —H -Me —N(CH₂—CH₂—OH)₂ HC≡C—CH₂—O— C═O -Me -Me —H —H -Me—N(CH₂—CH₂—OH)₂ Me₂N— C═O -Me -Me —H —H -Me —N(CH₂—CH₂—OH)₂ Et₂N— C═O-Me -Me —H —H -Me —N(CH₂—CH₂—OH)₂

-Me -Me —H —H -Me —N(CH₂—CH₂—OH)₂

C═O -Me -Me —H —H -Me —N(CH₂—CH₂—OH)₂ Me₂N—CO—NMe- C═O -Me -Me —H —H -Me—N[(CH₂)₂—SO₂—— (CH₂)₂—OH]₂ Me-CH₂-Me-CH—O— C═O -Me -Me —H —H -Me—N[(CH₂)₂—SO₂— (CH₂)₂—OH]₂ H₂C═CH—CH₂—O— C═O -Me -Me —H —H -Me—N[(CH₂)₂—SO₂— (CH₂)₂—OH]₂ H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me—N[(CH₂)₂—SO₂— (CH₂)₂—OH]₂ H₂C═CMe-O— C═O -Me -Me —H —H -Me—N[(CH₂)₂—SO₂— (CH₂)₂—OH]₂ HC≡C—CH₂—O— C═O -Me -Me —H —H -Me—N[(CH₂)₂—SO₂— (CH₂)₂—OH]₂ Me₂N— C═O -Me -Me —H —H -Me —N[(CH₂)₂—SO₂—(CH₂)₂—OH]₂ Et₂N— C═O -Me -Me —H —H -Me —N[(CH₂)₂—SO₂— (CH₂)₂—OH]₂

-Me -Me —H —H -Me —N[(CH₂)₂—SO₂—(CH₂)₂—OH]₂

C═O -Me -Me —H —H -Me —N[(CH₂)₂—SO₂—(CH₂)₂—OH]₂ Me₂N—CO—NMe- C═O -Me -Me—H —H -Me

Me-CH₂-Me-CH—O— C═O -Me -Me —H —H -Me

H₂C═CH—CH₂—O— C═O -Me -Me —H —H -Me

H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me

H₂C═CMe-O— C═O -Me -Me —H —H -Me

HC≡C—CH₂—O— C═O -Me -Me —H —H -Me

Me₂N— C═O -Me -Me —H —H -Me

Et₂N— C═O -Me -Me —H —H -Me

-Me -Me —H —H -Me

C═O -Me -Me —H —H -Me

Me₂N—CO—NMe- C═O -Me -Me —H —H -Me

Me-CH₂-Me-CH—O— C═O -Me -Me —H —H -Me

H₂C═CH—CH₂—O— C═O -Me -Me —H —H -Me

H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me

H₂C═CMe-O— C═O -Me -Me —H —H -Me

HC≡C—CH₂—O— C═O -Me -Me —H —H -Me

Me₂N— C═O -Me -Me —H —H -Me

Et₂N— C═O -Me -Me —H —H -Me

-Me -Me —H —H -Me

C═O -Me -Me —H —H -Me

Me₂N—CO—NMe- C═O -Me -Me —H —H -Me

Me₂N—CO—NMe- C═O -Me -Me —H —H -Me

Me-CH₂-Me-CH—O— C═O -Me -Me —H —H -Me

H₂C═CH—CH₂—O— -Me -Me —H —H -Me

H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me

H₂C═CMe-O— C═O -Me -Me —H —H -Me

HC≡C—CH₂—O— C═O -Me -Me —H —H -Me

Me₂N— C═O -Me -Me —H —H -Me

Et₂N— C═O -Me -Me —H —H -Me

-Me -Me —H —H -Me

C═O -Me -Me —H —H -Me

Me₂N—CO—NMe- C═O -Me -Me —H —H -Me

Me-CH₂-Me-CH—O— C═O -Me -Me —H —H -Me

H₂C═CH—CH₂—O— -Me -Me —H —H -Me

H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me

H₂C═CMe-O— C═O -Me -Me —H —H -Me

HC≡C—CH₂—O— C═O -Me -Me —H —H -Me

Me₂N— C═O -Me -Me —H —H -Me

-Me -Me —H —H -Me

C═O -Me -Me —H —H -Me

Me₂N—CO—NMe- C═O -Me -Me —H —H -Me

Me-CH₂-Me-CH—O— C═O -Me -Me —H —H -Me

H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me

Me₂N—CO—NMe- C═O -Me -Me —H —H -Me

Me-CH₂-Me-CH—O— C═O -Me -Me —H —H -Me

H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me

Me₂N—CO—NMe- C═O -Me -Me —H —H -Me

Me-CH₂-Me-CH—O— C═O -Me -Me —H —H -Me

H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me

Me₂N—CO—NMe- C═O -Me -Me —H —H -Me

Me-CH₂-Me-CH—O— C═O -Me -Me —H —H -Me

H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me

Me₂N—CO—NMe- C═O -Me -Me —H —H -Me

Me-CH₂-Me-CH—O— C═O -Me -Me —H —H -Me

H₂C═CH—CH₂—O— -Me -Me —H —H -Me

H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me

H₂C═CMe-O— C═O -Me -Me —H —H -Me

HC≡C—CH₂—O— C═O -Me -Me —H —H -Me

Me₂N— C═O -Me -Me —H —H -Me

-Me -Me —H —H -Me

C═O -Me -Me —H —H -Me

SO₂ -Me -Me —H —H -Me —O-Me Et₂N SO₂ -Me -Me —H —H -Me —O-MeMe₂N—CO—NMe- C═O -Me -Me —H —H -Me

Me-CH₂-Me-CH—O— C═O -Me -Me —H —H -Me

H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me

H₂C═CMe-O— C═O -Me -Me —H —H -Me

HC≡C—CH₂—O— C═O -Me -Me —H —H -Me

Me₂N— C═O -Me -Me —H —H -Me

-Me -Me —H —H -Me

C═O -Me -Me —H —H -Me

Me₂N—CO—NMe- C═O -Me -Me —H —H -Me

Me-CH₂-Me-CH—O— C═O -Me -Me —H —H -Me

H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me

H₂C═CMe-O— C═O -Me -Me —H —H -Me

HC≡C—CH₂—O— C═O -Me -Me —H —H -Me

Me₂N— C═O -Me -Me —H —H -Me

-Me -Me —H —H -Me

Et₂N—CO—NMe- C═O -Me -Me —H —H -Me

Me-CH₂-Me-CH—O— C═O -Me -Me —H —H -Me

H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me

H₂C═CMe-O— C═O -Me -Me —H —H -Me

HC≡C—CH₂—O— C═O -Me -Me —H —H -Me

Me₂N— C═O -Me -Me —H —H -Me

Me₂N— SO₂ -Me -Me —H —H -Me

Et₂N—CO—NMe- C═O -Me -Me —H —H -Me

Me₂N—CO—NMe- C═O -Me -Me —H —H -Me

Me-CH₂-MeCH—O— C═O -Me -Me —H —H -Me

H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me

H₂C═CMe-O— C═O -Me -Me —H —H -Me

HC≡C—CH₂—O— C═O -Me -Me —H —H -Me

Me₂N— C═O -Me -Me —H —H -Me

Me₂N— SO₂ -Me -Me —H —H -Me

Me₂N—CO—NMe- C═O -Me -Me —H —H -Me

Et₂N—CO—NMe- C═O -Me -Me —H —H -Me

Me-CH₂-Me-CH—O— C═O -Me -Me —H —H -Me

H₂C═CH—CHMe-O— C═O -Me -Me —H —H -Me

H₂C═CMe-O— C═O -Me -Me —H —H -Me

HC≡C—CH₂—O— C═O -Me -Me —H —H -Me

Me₂N C═O -Me -Me —H —H -Me

Me₂N SO₂ -Me -Me —H —H -Me

[0389] If, in process 3a for the preparation of the new didepsipeptides(Ia), as compounds of the general formula (II)N-methyl-N-trimethylallophanoyl-L-alanine and as compounds of thegeneral formula (III) isobutyl D-lactate are employed, the process canbe represented by the following reaction scheme:

[0390] Formula (II) provides a general definition of theN-terminal-acylated N-alkyl-amino acids needed as starting substancesfor carrying out process 3a according to the invention. In this formula,R¹, R², R³, G, Q and X preferably represent those radicals which havealready been mentioned as preferred for these substituents in connectionwith the description of the substances of the general formula (II)according to the invention.

[0391] The N-acylated N-alkyl-amino acids of the general formula (II)used as starting materials are known in some cases (cf. for example:N-methylamino acids: R. Bowmann et al. J. Chem. Soc. (1950) p. 1346, J.R. McDermott et al. Can. J. Chem. 51 (1973) p. 1915; H. Wurziger et al.Kontakte (Merck, Darmstadt) 3 (1987) p. 8) or can be obtained by theprocesses described there.

[0392] Formula (III) provides a general definition of the carboxylicacid derivatives additionally to be used as starting substances forcarrying out process 3a according to the invention.

[0393] In the formula (III), R⁴, R⁵, B and Z have the meaning which havealready been mentioned as preferred for these substituents in connectionwith the description of the substances of the general formula (Ia)according to the invention.

[0394] The compounds of the formula (III) are generally known compoundsof organic chemistry or can be obtained by methods known from theliterature (e.g.: 2-hydroxycarboxylic acid derivatives: cf. Houben-Weyl,Methoden der organischen Chermie, Volume VIII; 2-halogenocarboxylic acidderivatives: S. M. Birnbaum et al. J. Amer. Chem. Soc. 76 (1954) p.6054, C. S. Rondestvedt, Jr. et al. Org. Reactions 11 (1960) p. 189[Review]) or can be obtained by the processes described there.

[0395] The reaction of the N-acylated N-alkylamino acids (II) with2-hydroxycarboxylic acid derivatives (III) is preferably carried outusing diluents in the presence of coupling reagents and in the presenceof a basic reaction auxiliary.

[0396] The coupling reagents used for carrying out process 3a are allthose which are suitable for the preparation of an amide bond (cf. forexample: Houben-Weyl, Methoden der organischen Chemie [Methods ofOrganic Chemistry], Volume 15/2; Bodanszky et al., Peptide Synthesis 2nded. (Wiley & Sons, New York 1976) or Gross, Meienhofer, The Peptides:Analysis Synthesis, Biology (Academic Press, New York 1979). Thefollowing methods are preferably used: active ester method usingpentachlorophenol (Pcp) and pentafluorophenol (Pfp),N-hydroxysuccinimide, N-hydroxy-5-norbornene-2,3-dicarbox-amide (HONB),1-hydroxy-benzotriazole (HOBt) or3-hydroxy-4-oxo-3,4-dihydro1,2,3-benzotriazine as the alcohol component,coupling using carbodiimides such as dicyclohexyl-carbodiimide (DCC)according to the DCC additive process, or using n-propanephos-phonicanhydride (PPA) and mixed anhydride method using pivaloyl chloride,ethyl chloroformate (EEDQ) and isobutyl chloroformate (IIDQ) or couplingusing phosphonium reagents, such asbenzotriazol-1-yl-oxy-tris(dimethylamino-phosphonium)hexafluorophosphate (BOP), bis(2-oxo-3-oxazolidinyl)phosphonium acidchloride (BOP-Cl), or using phosphonic acid ester reagents, such asdiethyl cyanophosphonate (DEPC) and diphenylphosphoryl azide (DPPA) oruronium reagents, such as2-(1H-benzotrinazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoro borate(TBTU).

[0397] The preferred coupling is using phosphonium reagents such asbis(2-oxo-3-oxazolidinyl)-phosphonium acid chloride (BOP-Cl),benzotriazol-1-yl-oxy-tris(dimethylamino-phosphonium)hexafluorophosphate (BOP) and phosphonic acid ester reagents, such asdiethyl cyanophosphonate (DEPC) or diphenylphosphoryl azide (DPPA).

[0398] Basic reaction auxiliaries which can be employed for carrying outprocess 3a according to the invention are all suitable acid-bindingagents, such as amines, in particular tertiary amines, and alkali metaland alkaline earth metal compounds.

[0399] Examples which may therefore be mentioned are the hydroxides,oxides and carbonates of lithium, sodium, potassium, magnesium, calciumand barium, and further other basic compounds such as amidine bases orguanidine bases such as 7-methyl-1,5,7-triazabi-cyclo(4.4.0)dec-5-ene(MTBD); diazabicyclo(4.3.0)nonene (DBN), diazabicyclo(2.2.2)-octane(DABCO), 1,8-diaza-bicyclo(5.4.0)undecene (DBU)cyclohexyl-tetrabutylguanidine (CyTGB), cyclohexyltetramethylguanidine(CyTMG), N,N,N,N-tetramethyl-1,8-naphthalenediamine,pentamethylpiperidine, tertiary amines such as triethylamine,trimethylamine, tribenzylamine, triisopropylamine, tributylamine,tribenzylamine, tricyclohexylamine, triamylamine, trihexylamine,N,N-dimethyl-aniline, N,N-dimethyl-toluidine,N,N-dimethyl-p-aminopyridine, N-methyl-pyrrolidine, N-methyl-piperidine,N-methyl-imidazole, N-methyl-pyrrole, N-methyl-morpholine,N-methyl-hexamethyleneimine, pyridine, 4-pyrrolidinopyridine,4-dimethylamino-pyridine, quinoline, α-picoline, α-picoline,isoquinoline, pyrimidine, acridine, N,N,N′,N′-tetramethylenediamine,N,N′,N′-tetraethylenediamine, quinoxaline, N-propyl-diisopropylamine,N-ethyl-diisopropylamine, N,N′-dimethylcyclohexylamine, 2,6-lutidine,2,4-lutidine or triethylenediamine.

[0400] Those preferably used are tertiary amines, in particulartrialkylamines such as triethylamine, N,N-diisopropylethylamine,N-propyl-diisopropylamine, N,N′-dimethyl-cyclohexylamine orN-methylmorpholine.

[0401] In general, it is advantageous to carry out process 3a accordingto the invention in the presence of diluents. Diluents areadvantageously employed in an amount such that the reaction mixtureremains readily stirrable during the whole process. Suitable diluentsfor carrying out process 3a according to the invention are all inertorganic solvents.

[0402] Examples which may be mentioned are: halogenohydrocarbons, inparticular chlorohydrocarbons, such as tetrachloroethylene,tetrachloroethane, dichloropropane, methylene chloride, dichlorobutane,chloroform, carbon tetrachloride, trichloroethane, trichloroethylene,pentachloroethane, difluorobenzene, 1,2-dichloroethane, chlorobenzene,dichlorobenzene, chlorotoluene, trichlorobenzene; alcohols such asmethanol, ethanol, isopropanol, butanol; ethers such as ethyl propylether, methyl tert-butyl ether, n-butyl ether, anisole, phenetole,cyclohexyl methyl ether, dimethyl ether, diethyl ether, dipropyl esther,diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether,ethylene glycol dimethyl ether, tetrahydrofuran, dioxane,dichlorodiethyl ether and polyethers of ethylene oxide and/or propyleneoxide; amines such as trimethylamine, triethylamine, tripropylamine,tributylamine, N-methyl-morpholine, pyridine and tetramethylenediamine,nitrohydrocarbons such as nitromethane, nitroethane, nitropropane,nitrobenzene, chloronitrobenzene, o-nitrotoluene; nitriles such asacetonitrile, propionitrile, butyronitrile, isobutyronitrile,benzonitrile, m-chloro-benzonitrile, and compounds such astetrahydrothiophene dioxide and dimethyl sulphoxide, tetramethylenesulphoxide, dipropyl sulphoxide, benzyl methyl sulphoxide, diisobutylsulphoxide, dibutyl sulphoxide, diisoamyl sulphoxide; sulphones such asdimethyl sulphone, diethyl sulphone, dipropyl sulphone, dibutylsulphone, diphenyl sulphone, dihexyl sulphone, methyl ethyl sulphone,ethyl propyl sulphone, ethyl isobutyl sulphone and pentamethylenesulphone; aliphatic, cycloaliphatic or aromatic hydrocarbons such aspentane, hexane, heptane, octane, nonane and industrial hydrocarbons,for example so-called white spirits having components with boilingpoints in the range, for example, 40 to 250° C., cymene, benzinefractions within a boiling point interval from 70° C. to 190° C.,cyclohexane, methylcyclohexane, petroleum ether, ligroin, octane,benzene, toluene, xylene; esters such as methyl acetate, ethyl acetate,butyl acetate, isobutyl acetate, and also dimethyl carbonate, dibutylcarbonate, ethylene carbonate; amides such ashexamethylenephosphoramide, formamide, N-methylformamide,N,N-di-methylformamide, N,N-dipropylformamide, N,N-dibutylformamide,N-methyl-pyrrolidone, N-methyl-caprolactam,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidone,octylcaprolactam, 1,3-dimethyl-2-imidazolinedione, N-formylpiperidine,N,N′-1,4-diformylpiperazine; ketones such as acetone, methyl ethylketone, methyl butyl ketone.

[0403] Of course, mixtures of the solvents and diluents mentioned canalso be employed in the process according to the invention.

[0404] Preferred diluents are halogenohydrocarbons, in particularchlorohydrocarbons, such as methylene chloride or 1,2-dichloroethane andmixtures of these with other diluents mentioned.

[0405] Process 3a is in general carried out by reacting compounds of theformula (II) with compounds of the general formula (III) in one of thegiven diluents in the presence of one of the given coupling reagents andin the presence of one of the given basic auxiliaries. The reaction timeis 4 to 72 hours. The reaction is carried out at temperatures between−10° C. and +120° C., preferably between −5° C. and +50° C.,particularly preferably at 0° C. to room temperature. It is carried outunder normal pressure.

[0406] For carrying out process 3a according to the invention, ingeneral 1.0 to 3.0 mol, preferably 1.0 to 1.5 mol, of coupling reagentare employed per mole of N-acylated N-alkylamino acid of the formula(II).

[0407] After reaction is complete, the reaction solution is washed, andthe organic phase is separated off, dried and concentrated in vacuo. Theproducts formed can be purified in a customary manner byrecrystallization, vacuum distillation or column chromatography (cf.also the Preparation Examples).

[0408] Alternatively, the didepsipeptides according to the invention canalso be prepared according to classical processes, for example that asis described by H.-G. Lerchen and H. Kunz (Tetrahedron Lett. 26 (43)(1985) p. 5257-5260; 28 (17) (1987) p. 1873-1876) utilizing theesterification method according to B. F. Gisin (Helv. Chim. Acta 56(1973) p. 1476).

[0409] If, in process 3b for the preparation of the new didepsipeptides(Ia) as compounds of the general formula (Ib) methylN-methyl-L-alanyl-D-lactate and as compounds of the general formula (IV)trimethylallophanoyl chloride are employed, the process can berepresented by the following reaction scheme:

[0410] Formula (Ib) provides a general definition of theN-terminal-deblocked didepsipeptides needed as starting substances forcarrying out process 3b according to the invention. In this formula, R¹,R², R³, R⁴, R⁵ and B preferably represent those radicals which havealready been mentioned as preferred for these substituents in connectionwith the description of the substances of the general formula (Ia)according to the invention.

[0411] The N-terminal-deblocked didepsipeptides of the general formula(Ib) used as starting materials are known in some cases (cf. DE-OS[German Published Specification] 4 341 991, DE-OS [German PublishedSpecification] 4 341 992, DE-OS [German Published Specification] 4 341992) or can be obtained from N-terminal-protected didepsipeptides by theprocesses described there.

[0412] Formula (IV) provides a general definition of the compoundsadditionally to be used as starting substances for carrying out process3b according to the invention.

[0413] In the formula (IV), G, X, Y, and W have the meaning which havealready been mentioned as preferred for these substituents in connectionwith the description of the substances of the general formula (Ia)according to the invention.

[0414] The compounds of the formula (IV) are generally known compoundsof organic chemistry or can be obtained by methods known from theliterature (e.g.: per-substituted allophanoyl halides: DE-OS [GermanPublished Specification] 2 008 116; carbamoyl chlorides: Liebigs Ann.299, p. 85; carbamates: Houben-Weyl, Methoden der organischen Chemie,Volume E 4).

[0415] The reaction of the compounds (Ib) with (IV) is preferablycarried out using diluents in the presence of a basic reactionauxiliary.

[0416] Diluents used for carrying out process 3b according to theinvention are the inert, aprotic solvents mentioned in process 3a, e.g.dioxane, acetonitrile or tetrahydrofuran but also halogenohydrocarbons,in particular chlorohydrocarbons, such as methylene chloride.

[0417] Basic reaction auxiliaries which can be used for carrying outprocess 3b according to the invention are all acid-binding agentsmentioned in process 3a, but preferably tertiary amines, in particulartrialkylamines such as triethylamine, N,N-diisopropylethylamineN-propyl-diisopropylamine, N,N′-dimethyl-cyclohexylamine orN-methylmorpholine.

[0418] Process 3b is carried out by reacting compounds of the generalformula (Ib) in the presence of a basic reaction auxiliary withcompounds of the general formula (IV) in one of the given diluents.

[0419] The reaction time is 4 to 72 hours. The reaction is carried outat temperatures between −10° C. and +150° C., preferably between −5° C.and +80° C., particularly preferably at 0° C. to room temperature. It iscarried out under normal pressure. For carrying out process 3b accordingto the invention, in general 1.0 to 3.0 mol, preferably 1.0 to 1.5 mol,of acylating agent are employed per mole of N-alkylamino acid of theformula (Ib).

[0420] After reaction is complete, the reaction solution is washed, andthe organic phase is separated off, dried and concentrated in vacuo. Theproducts formed can be purified in a customary manner byrecrystallization, vacuum distillation or column chromatography (cf.also the Preparation Examples).

[0421] If, in process 3c for the preparation of the new didepsipeptides(Ia), as compounds of the general formula (Ib) tert-butylN-methyl-L-alanyl-D-lactate and as compounds of the general formula (V)trichloroacetyl isocyanate are employed, the process can be representedby the following reaction scheme:

[0422] Formula (Ib) provides a general definition of theN-terminal-deblocked didepsipeptides needed as starting substances forcarrying out process 3c according to the invention. In this formula, R¹,R², R³, R⁴, R⁵ and B preferably represent those radicals which havealready been mentioned as preferred for these substituents in connectionwith the description of the substances of the general formula (Ia)according to the invention.

[0423] The N-terminal-deblocked didepsipeptides of the general formula(Ib) used as starting materials are known in some cases (cf. DE-OS[German Published Specification] 4 341 991, DE-OS [German PublishedSpecification] 4 341 992, DE-OS [German Published Specification] 4 341992) or can be obtained from N-terminal-protected didepsipeptides by theprocesses described there.

[0424] Formulae (V) and (VI) provide a general definition of thecompounds additionally to be used as starting substances for carryingout process 3c according to the invention.

[0425] In the formula (VI), R⁸, Y, G¹, X¹ and X have the meaning whichhas already been mentioned as preferred for these substituents inconnection with the description of the substances of the general formula(Ia) according to the invention.

[0426] The compounds of the formula (VI) are generally known compoundsof organic chemistry and can be obtained commercially in some cases orby methods known from the literature (Houben-Weyl, Methoden derorganischen Chemie, [Methods of organic chemistry] Volume E4).

[0427] The reaction of the compounds (Ib) with (VI) by process 3caccording to the invention is preferably carried out in the presence ofdiluents, if appropriate in the presence of a basic reaction auxiliary.

[0428] Diluents used for carrying out process 3c according to theinvention are the solvents mentioned in process 3a, e.g. nitriles suchas acetonitrile, propionitrile, butyronitrile, in particularacetonitrile, and ethers such as ethyl propyl ether, n-butyl ether,diethyl ether, dipropyl esther, diisopropyl ether, di-n-butyl ether,diisobutyl ether, diisoamyl ether, tetrahydrofuran, dioxane, inparticular terahydrofuran and dioxane.

[0429] Process 3c can also be carried out in the presence of basicreaction auxiliaries. Those basic reaction auxiliaries which can use forcarrying out process 3c according to the invention are all acid-bindingagents mentioned in process 3a, but preferably tertiary amines, inparticular trialkylamines such as triethylamine,N,N-diisopropylethylamine or N-methylmorpholine, and amidine bases orguanidine bases such as diazabicyclo-(4.3.0)nonene (DBN), diazabicyclo(2.2.2)-octane (DABCO), 1,8-diazabicyclo(5.4.0)-undecene (DBU), inparticular 1,8-diazabicyclo(5.4.0)-undecene (DBU), use.

[0430] Process 3c is carried out by combining compounds of the generalformula (Ib) with equimolar amounts of a compound of the formula (VI) inone of the diluents given above, if appropriate in the presence of abasic reaction auxiliary. The reaction time is 1 to 72 hours. Thereaction is carried out at temperatures between −50° C. to +200° C.,preferably in a temperature range between −20° C. and +150° C., inparticular in a temperature range between −10° C. and +120° C.

[0431] Fundamentally, it can be carried out under normal pressure, butalso at elevated or reduced pressure. The process is preferably carriedout at normal pressure or at pressures of up to 15 bar. At highertemperatures, it is advantageous to work at elevated pressure, ifappropriate even above 15 bar.

[0432] After reaction is complete, the reaction mixture is worked up bygenerally customary methods (cf. also the Preparation Examples).

[0433] Processes for the preparation of organic carbamates from an aminehaving a basic reaction, carbon dioxide and an alkylating agent in thepresence of basic alkali metal, alkaline earth metal or ammonium saltsare known (cf. EP-OS [European Published Specification] 511 948, EP-OS[European Published Specification] 628 542 and literature cited there).

[0434] It has now been found that even the weakly basic,N-terminal-deblocked didepsipeptides of the formula (Ib) according tothe invention, as amino compounds, react with carbon dioxide and analkylating agent in the presence of metal carbamates to give carbamatesof the general formula (Ia).

[0435] If, in process 3d for the preparation of the new didepsipeptides(Ia), as compounds of the general formula (Ib) tert-butylN-methyl-L-alanyl-D-lactate, carbon dioxide, potassium carbonate and ascompounds of the general formula (IX) butyl bromide are employed, theprocess can be represented by the following reaction scheme:

[0436] Preferably, in in process 3d the didepsipeptides of the formula(Ib) are employed in which the radicals R¹, R², R³, R⁴, R⁵ and B havethe preferred and particularly preferred meanings in the case of thecompounds of the general formula (Ia).

[0437] The N-terminal-deblocked didepsipeptides of the general formula(Ib) used as starting materials are known in some cases (cf. DE-OS[German Published Specification] 4 341 991, DE-OS [German PublishedSpecification] 4 341 992, DE-OS [German Published Specification] 4 341992) or can be obtained from N-terminal-protected didepsipeptides by theprocesses described there.

[0438] As carbon dioxide, the customary commercially available product,if appropriate alternatively so-called “dry ice”, can be employed in theprocess according to the invention.

[0439] The alkylating agents of the formula (IX) additionally to be usedas starting substances for carrying out process 3d according to theinvention are generally known compounds of organic chemistry. In formula(IX) R⁸ has the meaning which has already been mentioned as preferredfor these substituents in connection with the description of thesubstances of the general formula (Ia) according to the invention andHal has the meaning of an electron-withdrawing leaving group.

[0440] Suitable leaving groups are, for example, halogen, such asfluorine, chlorine, bromine and iodine, sulphonate such as aryl- andperfluoroalkylsulphonate, monosubstituted diazo and monosubstitutednitrato, and those additionally mentioned in J. March, Advanced OrganicChemistry, 3rd ed., John Wiley & Sons, New York 1985, pp. 310-316.

[0441] Compounds having a basic reaction which can be used in thepresent invention are one or more basic compounds of the elementslithium, sodium, magnesium, potassium, calcium, rubidium, strontium,caesium, barium, and/or of the ammonium ion. Suitable basic compoundsare, for example, salts, oxides, hydrides and hydroxides which have abasic reaction. Examples which may be mentioned are: lithium hydride,sodium hydride, potassium hydride, calcium hydride, lithium hydroxide,sodium hydroxide, potassium hydroxide, rubidium hydroxide, magnesiumhydroxide, calcium hydroxide, strontium hydroxide, barium hydroxide,lithium oxide, sodium peroxide, potassium oxide, potassium peroxide,calcium oxide, barium oxide, magnesium oxide, strontium oxide, lithiumcarbonate, lithium hydrogencarbonate, rubidium carbonate, rubidiumhydrogencarbonate, caesium hydrogencarbonate, caesium carbonate, lithiumcyanide, sodium cyanide, potassium cyanide, rubidium cyanide, ammoniumhydrogencarbonate, caesium carbonate, ammonium carbamate, potassiumsulphide, potassium hydrogensulphide, sodium sulphide, sodiumhydrogensulphide and/or their naturally occurring or syntheticallyobtainable mixtures, for example dolomite or magnesium oxide carbonateand/or compounds which contain sodium or potassium metal on thecorresponding carbonates in dispersed form.

[0442] Alkali metal carbonates and/or hydrogencarbonates, however, arepreferred, very particularly preferably caesium carbonate or potassiumcarbonate.

[0443] The compounds having a basic reaction can be employed inanhydrous form, or if they are salts which crystallize with water ofhydration, also in hydrated form. Preferably, however, anhydrouscompounds are used.

[0444] Diluents used for carrying out process 3d according to theinvention are the solvents mentioned in process 3a, e.g. amides such ashexamethylenephosphoramide, N,N-di-methylformamide,N,N-dipropylformamide, N,N-dibutylformamide, N-methyl-pyrrolidone orN-methyl-caprolactam, in particular N,N-dialkylformamides, such asN,N-dimethylformamide, and sulphoxides such as dimethyl sulphoxide,tetramethylene sulphoxide, dipropyl sulphoxide, benzyl methylsulphoxide, diisobutyl sulphoxide, dibutyl sulphoxide, diisoamylsulphoxide, in particular dimethyl sulphoxide.

[0445] Alternatively, process 3d can also be carried out in the presenceof basic reaction auxiliaries, i.e. in the presence of other bases, forexample in an amount of less than 0.5 mol, based on the base employed.

[0446] Those basic reaction auxiliaries which can use for carrying outprocess 3d according to the invention are all acid-binding agentsmentioned in process 3a, but preferably tertiary amines, in particulartrialkylamines such as triethylamine, N,N-diisopropylethylamine orN-methylmorpholine, and amidine bases or guanidine bases such as7-methyl-1,5,7-triazabi-cyclo(4.4.0)dec-5-ene (MTBD);diazabicyclo-(4.3.0)nonene (DBN), diazabicyclo(2.2.2)-octane (DABCO),1,8-diazabicyclo(5.4.0)-undecene (DBU) cyclohexyltetrabutylguanidine(CyTBG), cyclohexyltetramethylguani-dine (CyTMG),cyclohexyltetrabutylguanidine,N,N,N,N-tetramethyl-1,8-naphthalenediamine, in particularcyclohexyltetramethylguanidine (CyTMG) and cyclohexyltetrabutylguanidine(CyTBG).

[0447] Process 3d is carried out by combining compounds of the generalformula (Ib) at room temperature in the presence of carbon dioxide, a 2-to 3-fold excess of alkali metal carbonate of the formula (VII) and analkylating agent of the formula (IX) in one of the diluents given above,if appropriate in the presence of a basic reaction auxiliary. In asecond reaction step, the alkylation of the alkali metal salts of theformula (VIII) formed in situ with compounds of the formula (IX) takesplace during a reaction time of 1 to 72 hours and a reaction temperaturebetween −50 and +180° C.; temperatures in the range between −30 and+150° C. are preferred, in particular those in the range −10 to +100° C.

[0448] Fundamentally, it can be carried out under normal pressure, butit can also be carried out at elevated or reduced pressure. The processis preferably carried out at normal pressure or at pressures of up to 15bar. At higher temperatures, it is advantageous to work at elevatedpressure, if appropriate even above 15 bar.

[0449] The working-up and isolation of the reaction products is carriedout by generally customary methods (cf. also the Preparation Examples).

[0450] If, in a process 3e for the preparation of the newdidepsipeptides (Ia), as compounds of the general formula (Ic)tert-butyl N-methyl-N-(4-nitro-phenoxycarbonyl)-L-alanyl-D-lactate andas a nucleophile of the general formula (X) morpholine is employed, theprocess can be represented by the following reaction scheme:

[0451] Formula (Ie) provides a general definition of theN-terminal-acylated didepsipeptides needed as starting substances forcarrying out process 3e according to the invention. In this formula, R¹,R², R³, R⁴, R⁵, G, W, X and B preferably represent those radicals whichhave already been mentioned as preferred for these substituents inconnection with the description of the substances of the general formula(Ia) according to the invention.

[0452] The N-terminal-acylated didepsipeptides of the general formula(Ib) used as starting materials are known in some cases (cf. DE-OS[German Published Specification] 4 341 991, DE-OS [German PublishedSpecification] 4 341 992, DE-OS [German Published Specification] 4 341992), can be obtained by the processes described there or can beprepared by process 3b according to the invention shown above.

[0453] The nucleophilic agents of the formula (X) additionally to beused as starting substances for carrying out process 3e according to theinvention are generally known compounds of organic chemistry. In theformula (X), R⁸ and Y have the meaning which has already been mentionedas preferred in connection with the description of the substances of thegeneral formula (Ia) according to the invention.

[0454] Process 3e is carried out by reacting compounds of the generalformula (Ie) in the presence of a nucleophilic agent of the formula (X)in one of the diluents given above. The reaction time is 4 to 72 hours.The reaction is carried out at temperatures between +10° C. and +200°C., preferably between +20° C. and +150° C., particularly preferably atboiling temperature of the diluent.

[0455] Fundamentally, it can be carried out under normal pressure, butit can also be carried out at elevated or reduced pressure. The processis preferably carried out at normal pressure or at pressures of up to 15bar. At higher temperatures it is advantageous to work at elevatedpressure, if appropriate even above 15 bar.

[0456] After reaction is complete, the reaction solution is washed, andthe organic phase is separated off, dried and concentrated in vacuo. Theproducts which are formed can be purified in a customary manner byrecrystallization, vacuum distillation or column chromatography (cf.also the Preparation Examples).

[0457] If, in process 3f for the preparation of the new didepsipeptides(Ia), as compounds of the general formula (Id)N-methyl-N-trimethylallophanoyl-L-alanyl-D-lactic acid and as compoundsof the general formula (XI) L-homoproline methyl ester hydrochloride(H-Pec-OME.HCl) are employed, the process can be represented by thefollowing reaction scheme:

[0458] Formula (Id) provides a general definition of theC-terminal-deblocked didepsipeptides needed as starting substances forcarrying out process 3e according to the invention. In this formula, R¹,R², R³, R⁴, R⁵, G, X and Q preferably represent those radicals whichhave already been mentioned as preferred for these substituents inconnection with the description of the substances of the general formula(Ia) according to the invention.

[0459] The C-terminal-deblocked didepsipeptides of the general formula(Id) used as starting materials are known in some cases (cf. DE-OS[German Published Specification] 4 341 991, DE-OS [German PublishedSpecification] 4 341 992, DE-OS [German Published Specification] 4 341992) or can be obtained by the processes described there.

[0460] For example, the C-terminal-deblocked didepsipeptides (Id) usedas starting materials can be prepared by means of customary methods of aC-terminal deblocking such as acidolysis, for example in the case of atert-butyl ester, or catalytic hydrogenation, for example in the case ofa benzyl ester.

[0461] Formula (XI) provides a general definition of the nucleophilesadditionally to be used as starting substances for carrying out process3e according to the invention.

[0462] In the formula (XI), B has the meaning which has already beenmentioned as preferred for these substituents in connection with thedescription of the substances of the general formula (Ia) according tothe invention.

[0463] The compounds of the formula (XI) are generally known compoundsof organic chemistry and can be obtained commercially in some cases orby methods known from the literature.

[0464] The reaction of the C-terminal-deblocked didepsipeptides of theformula (Id) with compounds of the formula (XI) is preferably carriedout using diluents in the presence of coupling reagents and in thepresence of a basic reaction auxiliary.

[0465] Coupling reagents used for carrying out process 3f are allcoupling reagents suitable for the preparation of an amide bond andalready employed in process 3a mentioned above.

[0466] The preferred coupling is with phosphonium reagents such asbis(2-oxo-3-oxazolidinyl)-phosphonium acid chloride (BOP-Cl),benzotriazol-1-yl-oxy-tris(dimethylamino-phosphonium)hexafluorophosphate (BOP) and phosphonic acid ester reagents, such asdiethyl cyanophosphonate (DEPC) or diphenylphosphoryl azide (DPPA).

[0467] Basic reaction auxiliaries which can be employed for carrying outprocess 3f according to the invention are also all acid-binding agentssuitable for process 3a.

[0468] Preferably, tertiary amines, in particular trialkylamines such astriethylamine N,N-diisopropylethylamine, N-propyl-diisopropylamine,N,N′-dimethyl-cyclohexylamine or N-methylmorpholine are suitable.

[0469] Diluents used for carrying out process 3f according to theinvention are the solvents mentioned in process 3e, e.g.halogenohydrocarbons, in particular chlorohydrocarbons, such asmethylene chloride of 1,2-dichloroethane and mixtures of these withother diluents mentioned.

[0470] Process 3j is in general carried out by reacting compounds of theformula (Id) with compounds of the general formula (XI) in one of thegiven diluents in the presence of one of the given coupling reagents andin the presence of one of the given basic reaction auxiliaries. Thereaction time is 4 to 72 hours. The reaction is carried out attemperatures between −10° C. and +120° C., preferably between −5° C. and+50° C., particularly preferably at 0° C. to room temperature. It iscarried out under normal pressure.

[0471] In general 1.0 to 3.0 mol, preferably 1.0 to 1.5 mol, of couplingreagent are employed per mole of C-terminal-deblocked didepsipeptide ofthe formula (Id) for carrying out process 3f according to the invention.

[0472] After reaction is complete, the reaction solution is washed, andthe organic phase is separated off, dried and concentrated in vacuo. Theproducts which are formed can be purified in a customary manner byrecrystallization, vacuum distillation or column chromatography (cf.also the Preparation Examples).

[0473] Using processes 3a to 3f according to the invention,didepsipeptides of both L- and D-configuration are obtainable from theindividual components, retaining the original configuration but alsoinversion is possible of the starting substances.

[0474] By the “inert solvents” described in the above process variants3a to 3f, in each case solvents are meant which are inert under therespective reaction conditions, but do not have to be inert under anyreaction conditions.

[0475] The active compounds have favourable toxicity for warm-bloodedmammals and are suitable for controlling pathogenic endoparasites whichoccur in humans and in productive, breeding, zoo, laboratory,experimental animals and pets in animal keeping and animal breeding. Inthis connection, they are resistant to all or individual stages ofdevelopment of the pests and to resistant and normally sensitivestrains. By controlling the pathogenic endoparasites, disease, cases ofdeath and yield reductions (e.g. in the production of meat, milk, wool,hides, eggs, honey etc.) should be decreased so that as a result of theuse of the active compounds more economical and simpler animal keepingis possible. The pathogenic endoparasites include cestodes, trematodes,nematodes, Acantocephalae, in particular:

[0476] From the order of the Pseudophyllidea, e.g.: Diphyllobothriumspp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridiumspp. Diphlogonoporus spp..

[0477] From the order of the Cyclophyllidea e.g.: Mesocestoides spp.,Anoplocephala spp., Paranoplocephala spp., Moniezia spp., ‘Thysanosomsaspp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaeniaspp., Andyra spp., Bertiella spp., Taenia spp., Echinococcus spp.,Hydatigera spp., Davainea spp., Raillietina spp., Hymenolepis spp.,Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp.,Joyeuxiella spp., Diplopylidium spp..

[0478] From the subclass of the Monogenea, e.g. Gyrodactylus spp.,Dactylogyrus spp., Polystoma spp..

[0479] From the subclass of the Digenea e.g.: Diplostomum spp.,Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp.,Ornithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp.,Leucochloridium spp., Brachylaima spp., Echinostoma spp.,Echinoparyphium spp., Echinochasmus spp., Hypoderaeum spp., Fasciolaspp., Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp.,Typhlocoelum spp., Paramphistomum spp., Calicophoron spp., CotyLophoronspp., Gigantocotyle spp., Fischoederius spp., Gastrothylacus spp.,Notocotylus spp., Catatropis spp., Plagiorchis spp., Prosthogonimusspp., Dicrocoelium spp., Eurytrema spp., Troglotrema spp., Paragonimusspp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchisspp., Metorchis spp., Heterophyes spp., Metagonismus spp..

[0480] From the order of the Enoplida e.g.: Trichuris spp., Capillariaspp., Trichomosoides spp., Trichinella spp..

[0481] From the order of the Rhabditia e.g.: Micronema spp.,Strongyloides spp..

[0482] From the order of the Strongylida e.g.: Stronylus spp.,Triodontophorus spp., Oesophagodontus spp., Trichonema spp.,Gyalocephalus spp., Cylindropharynx spp., Poteriostomum spp.,Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp.,Chabertia spp., Stephanurus spp., Ancylostoma spp., Uncinaria spp.,Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostoma spp.,Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylusspp., Neostrongylus spp., Cystocaulus spp., Pneumostrongylus spp.,Spicocaulus spp., Elaphostrongylus spp., Parelaphostrongylus spp.,Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp.,Aelurostrongylus spp., Filaroides spp., Parafilaroides spp.,Trichostrongylus spp., Haemonchus spp., Ostertagia spp:, Marshallagiaspp., Cooperia spp., Nematodirus spp., Hyostrongylus spp., Obeliscoidesspp., Amidostomum spp., Ollulanus spp..

[0483] From the order of the Oxyurida e.g.: Oxyuris spp., Enterobiusspp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp.,

[0484] From the order of the Ascaridia e.g.: Ascaris spp., Toxascarisspp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp..

[0485] From the order of the Spirurida e.g.: Gnathostoma spp.,Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp.,Parabronema spp., Draschia spp., Dracunculus spp..

[0486] From the order of the Filariida e.g.: Stephanofilaria spp.,Parafilaria spp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoidesspp., Brugia spp., Wuchereria spp., Onchocerca spp..

[0487] From the order of Gigantorhynchida e.g.: Filicollis spp.,Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp..

[0488] The productive and breeding animals include mammals such ascattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys,rabbits, fallow deer, reindeer, fur-bearing animals such as mink,chinchilla, raccoon, birds such as hens, geese, turkeys, ducks, fresh-and salt-water fish such as trout, carp, eels, reptiles, insects such ashoney bees and silkworms.

[0489] Laboratory and experimental animals include mice, rats,guinea-pigs, golden hamsters, dogs and cats.

[0490] The pets include dogs and cats.

[0491] Administration can be carried out both prophylactically andtherapeutically.

[0492] Administration of the active compounds is carried out, directlyor in the form of suitable preparations, enterally, parenterally,dermally, nasally, by treatment of the surroundings or with the aid ofactive compound-containing shaped articles such as strips, disks, tapes,collars, ear tags, limb bands, marking devices.

[0493] Enteral administration of the active compounds is carried out,for example, orally in the form of powders, tablets, capsules, pastes,drinks, granules, orally administrable solutions, suspensions andemulsions, boli, medicated feed or drinking water. Dermal administrationis carried out, for example, in the form of dipping, spraying orpouring-on and spotting-on. Parental administration is carried out, forexample, in the form of injection (intramuscular, subcutaneous,intravenous, intraperitoneal) or by implants.

[0494] Suitable preparations are:

[0495] solutions such as injection solutions, oral solutions,concentrates for oral administration after dilution, solutions for useon the skin or in body cavities, pouring-on formulations, gels;

[0496] emulsions and suspensions for oral or dermal administration andfor injection; semi-solid preparations;

[0497] formulations in which the active compound is processed in anointment base or in an oil-in-water or water-in-oil emulsion base;

[0498] Solid preparations such as powders, premixes or concentrates,granules, pellets, tablets, boli, capsules; aerosols and inhalants,active compound-containing shaped articles.

[0499] Injection solutions are administered intravenously,intramuscularly and sub-cutaneously.

[0500] Injection solutions are prepared by dissolving the activecompound in a suitable solvent and possibly adding additives such assolubilizers, acids, bases, buffer salts, antioxidants, preservatives.The solutions are sterile-filtered and bottled.

[0501] Solvents which may be mentioned are: pHysiologically tolerablesolvents such as water, alcohols such as ethanol, butanol, benzylalcohol, glycerol, propylene glycol, polyethylene glycols,N-methyl-pyrrolidone, and mixtures thereof.

[0502] The active compounds can optionally also be dissolved inphysiologically tolerable vegetable or synthetic oils which are suitablefor injection.

[0503] Solubilizers which may be mentioned are: solvents which promotethe dissolution of the active compound in the main solvent or preventits precipitation. Examples are polyvinylpyrrolidone, polyoxyethylatedcastor oil, polyoxyethylated sorbitan ester.

[0504] Preservatives are: benzyl alcohol, trichlorobutanol,p-hydroxybenzoic acid esters, n-butanol.

[0505] Oral solutions are administered directly. Concentrates areadministered orally after prior dilution to the use concentration. Oralsolutions and concentrates are prepared as described above in the caseof the injection solutions, where sterile working can be dispensed with.

[0506] Solutions for use on the skin are trickled on, spread on, rubbedin, sprinkled on or sprayed on. These solutions are prepared asdescribed above in the case of the injection solutions.

[0507] It can be advantageous to add thickeners during preparation.Thickeners are: inorganic thickeners such as bentonites, colloidalsilicic acid, aluminium monostearate, organic thickeners such ascellulose derivatives, polyvinyl alcohols and their copolymers,acrylates and methacrylates.

[0508] Gels are applied to or spread on the skin or introduced into bodycavities. Gels are prepared by treating solutions which have beenprepared as described in the case of the injection solutions withsufficient thickener that a clear material having an ointment-likeconsistency results. The thickeners employed are the thickeners givenabove.

[0509] Pouring-on formulations are poured or sprayed onto limited areasof the skin, the active compound penetrating the skin and actingsystemically.

[0510] Pouring-on formulations are prepared by dissolving, suspending oremulsifying the active compound in suitable skin-compatible solvents orsolvent mixtures. If appropriate, other auxiliaries such as colourants,absorption-promoting substances, antioxidants, sunscreens, adhesives areadded.

[0511] Solvents which may be mentioned are: water, alkanols, glycols,polyethylene glycols, polypropylene glycols, glycerol, aromatic alcoholssuch as benzyl alcohol, phenylethanol, phenoxyethanol, esters such asethyl acetate, butyl acetate, benzyl benzoate, ethers such as alkyleneglycol alkyl ethers such as dipropylene glycol monomethyl ether,diethylene glycol mono-butyl ether, ketones such as acetone, methylethyl ketone, aromatic and/or aliphatic hydrocarbons, vegetable orsynthetic oils, DMF, dimethylacetamide, N-methylpyrrolidone,2,2-dimethyl-4-oxy-methylene-1,3-dioxolane.

[0512] Colourants are all colourants permitted for use on animals andwhich can be dissolved or suspended.

[0513] Absorption-promoting substances are, for example, DMSO, spreadingoils such as isopropyl myristate, dipropylene glycol pelargonate,silicone oils, fatty acid esters, triglycerides, fatty alcohols.

[0514] Antioxidants are sulphites or metabisulphites such as potassiummetabisulphite, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole,tocopherol.

[0515] Sunscreens are, for example, novantisolic acid.

[0516] Adhesives are, for example, cellulose derivatives, starchderivatives, polyacrylates, natural polymers such as alginates, gelatin.

[0517] Emulsions can be administered orally, dermally or as injections.

[0518] Emulsions are either of the water-in-oil type or of theoil-in-water type.

[0519] They are prepared by dissolving the active compound either in thehydrophobic or in the hydrophilic phase and homogenizing this with thesolvent of the other phase with the aid of suitable emulsifiers and, ifappropriate, other auxiliaries such as colourants, absorption-promotingsubstances, preservatives, antioxidants, sunscreens, viscosity-enhancingsubstances.

[0520] Hydrophobic phases (oils) which may be mentioned are: liquidparaffins, silicone oils, natural vegetable oils such as sesame oil,almond oil, castor oil, synthetic triglycerides such as caprylic/capricbiglyceride, triglyceride mixture with vegetable fatty acids of thechain length C₈₋₁₂ or other specially selected natural fatty acids,partial glyceride mixtures of saturated or unsaturated fatty acidspossibly also containing hydroxyl groups, mono- and diglycerides of theC₈/C₁₀ fatty acids.

[0521] Fatty acid esters such as ethyl stearate, di-n-butyryl adipate,hexyl laurate, dipropylene glycol perlargonate, esters of a branchedfatty acid of medium chain length with saturated fatty alcohols of chainlength C₁₆-C₁₈, isopropyl myristate, isopropyl palmitate,caprylic/capric acid esters of saturated fatty alcohols of chain lengthC₁₂-C₁₈, isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate,ethyl lactate, waxy fatty acid esters such as synthetic duck coccygealgland fat, dibutyl phthalate, diisopropyl adipate, ester mixturesrelated to the latter, inter alia.

[0522] Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol,cetylstearyl alcohol, oleyl alcohol.

[0523] Fatty acids such as oleic acid and its mixtures.

[0524] Hydrophilic phases which may be mentioned are: water, alcoholssuch as propylene glycol, glycerol, sorbitol and its mixtures.

[0525] Emulsifiers which may be mentioned are: non-ionic surfactants,e.g. polyethoxylated castor oil, polyethoxylated sorbitan monooleate,sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate,alkylphenol polyglycol ether;

[0526] ampholytic surfactants such as di-Na N-lauryl-β-iminodipropionateor lecithin;

[0527] anionic surfactants, such as Na lauryl sulphate, fatty alcoholether sulphates, mono/dialkyl polyglycol ether orthophosphoric acidester monoethynolamine salt.

[0528] Further auxiliaries which may be mentioned are: substances whichenhance the viscosity and stabilize the emulsion, such ascarboxymethylcellulose, methylcellulose and other cellulose and starchderivatives, polyacrylates, alginates, gelatin, gum arabic,polyvinylpyrrolidone, polyvinyl alcohol, copolymers of methyl vinylether and maleic anhydride, polyethylene glycols, waxes, colloidalsilicic acid or mixtures of the substances mentioned.

[0529] Suspensions can be administered orally, dermally or as aninjection. They are prepared by suspending the active compound in asuspending agent, if appropriate with addition of other auxiliaries suchas wetting agents, colourants, absorption-promoting substances,preservatives, antioxidants light screens.

[0530] Suspending agents which may be mentioned are all homogeneoussolvents and solvent mixtures.

[0531] Wetting agents (dispersants) which may be mentioned are thesurfactants given above.

[0532] Other auxiliaries which may be mentioned are those given above.

[0533] Semi-solid preparations can be administered orally or dermally.They differ from the suspensions and emulsions described above only bytheir higher viscosity.

[0534] For the production of solid preparations, the active compound ismixed with suitable excipients, if appropriate with addition ofauxiliaries, and brought into the desired form.

[0535] Excipients which may be mentioned are all physiologicallytolerable solid inert substances. Those used are inorganic and organicsubstances. Inorganic substances are, for example, sodium chloride,carbonates such as calcium carbonate, hydrogencarbonates, aluminiumoxides, silicic acids, argillaceous earths, precipitated or colloidalsilica, phosphates.

[0536] Organic substances are, for example, sugar, cellulose, foodstuffsand feeds such as milk powder, animal meal, grain meals and shreds,starches.

[0537] Auxiliaries are preservatives, antioxidants, colourants whichhave already been mentioned above.

[0538] Other suitable auxiliaries are lubricants and glidants such asmagnesium stearate, stearic acid, talc, bentonites,disintegration-promoting substances such as starch or crosslinkedpolyvinylpyrrolidone, binders such as starch, gelatin or linearpoly-vinylpyrrolidone, and dry binders such as microcrystallinecellulose.

[0539] The active compounds can also be present in the preparations as amixture with synergists or with other active compounds which act againstpathogenic endoparasites. Such active compounds are, for example,L-2,3,5,6-tetrahydro-6-phenylimidazolthiazole, benzimidazole carbamates,praziquantel, pyrantel, febantel.

[0540] Ready-to-use preparations contain the active compound inconcentrations of 10 ppm-20 percent by weight, preferably from 0.1-10percent by weight.

[0541] Preparations which are diluted before use contain the activecompound in concentrations of 0.5-90% by weight, preferably of 5-50% byweight.

[0542] In general, it has proved advantageous to administer amounts ofapproximately 1 to approximately 100 mg of active compound per kg ofbody weight per day to achieve effective results.

EXAMPLE 1

[0543] In vivo Nematode Test

[0544]Trichostrongylus colubriformis/Sheep

[0545] Sheep experimentally infected with Trichostrongylus colubriformiswere treated after expiry of the prepatency time of the parasite. Theactive compounds were administered orally and/or intravenously as pureactive compound.

[0546] The degree of effectiveness is determined by quantitativelycounting the worm eggs excreted with the faeces before and aftertreatment.

[0547] Complete cessation of oviposition after treatment means that theworms have been expelled or are so damaged that they no longer produceeggs (effective dose).

[0548] Active compounds tested and effective doses can be seen from thefollowing table. Active compound Effective dose Example No. in [mg/kg] 2 5  9 5 11 5 12 5 13 5 18 5 I - 7 5 46 5 68 5

EXAMPLE B

[0549] In vivi Nematode Test

[0550]Haemonchus contortus/Sheep

[0551] Sheep experimentally infected with Haemonchus contortus weretreated after expiry of the prepatency time of the parasite. The activecompounds were administered orally and/or intravenously as pure activecompound.

[0552] The degree of effectiveness is determined by quantitativelycounting the worm eggs excreted with the faeces before and aftertreatment.

[0553] Complete cessation of oviposition after treatment means that theworms have been expelled or are so damaged that they no longer produceeggs (effective dose).

[0554] Active compounds tested and effective doses can be seen from thefollowing tables. Active compound Effective dose Example No. in [mg/kg] 2 5  8 5  9 5 10 5 11 5 12 5 19 5 20 5 30 5 31 5 34 5 35 5 36 5 38 5 475 49 5 50 5 68 5 61 5 I - 4 5 I - 5 5 I - 7 5

PREPARATION EXAMPLES

[0555] Preparation by Process 3a

Example 1 Isobutyl N-methyl-N-trimethylallophanoyl-L-alanyl-D-lactate

[0556]

[0557] 2.9 g (22.9 mmol) of N,N-diisopropylethylamine (“Hünig's base”)and 2.9 g (11.4 mmol) of bis(2-oxo-3-oxazolidinyl)-phosphonium acidchloride (BOP-Cl) are added at 0° C. to a solution of 2.4 g (10.4 mmol)of N-methyl-N-trimethylallophanoyl-L-alanine and 1.5 g (10.4 mmol) ofisobutyl D-lactate in 20 ml of methylene chloride and the mixture isstirred at room temperature for 18 [lacuna]. The reaction solution isshaken twice with water, and the organic phase is separated off andconcentrated in vacuo after drying over sodium sulphate. The residualcrude product is chromatographed on a silica gel column (silica gel60—Merck, particle size: 0.04 to 0.063 mm) using the eluent cyclohexane:acetone (4:1). 1.6 g (57.2% of theory) of isobutylN-methyl-N-trimethylallophanoyl-L-alanyl-D-lactate are obtained.

[0558]¹H-NMR (400 MHz, CDCl₃, δ): 0.92; 0.94 (d, 6H, 2 x —CH₃; J=6.7Hz); 2.91; 2.92; 2.94 (3s, 9H, 3 x N—CH₃); 3.06 (s, 3H, —N—CH₃); 3.92(m, 3H, —O—CH₂)—; 5.14 (m, 1H, CH) ppm

[0559] GC-MS m/z (%): 360 (MH⁺, 100); 271 (38); 214 (62).

[0560] Preparation by Process 3b

Example 2 Methyl N-methyl-N-trimethylallophanoyl-L-alanyl-D-lactate

[0561]

[0562] 3.8 g (29.1 mmol) of N,N-diisopropylethylamine (“Hünig's base”)and 2.1 g (12.7 mmol) of trimethylallophanoyl chloride are added at 0°C. to a solution of 2.0 g (10.6 mmol) of methylN-methyl-L-alanyl-D-lactate in 100 ml of methylene chloride, and themixture is stirred at 0° C. for two hours and then at room temperaturefor about 18 hours. The reaction solution is shaken twice with water,and the organic phase is separated off and concentrated in vacuo afterdrying over sodium sulphate. The residual crude product ischromatographed on a silica gel column (silica gel 60—Merck, particlesize: 0.04 to 0.063 mm) using the eluent cyclohexane:ethyl acetate(3:1). 1.35 g (40.2% of theory) of methylN-methyl-N-trimethylallophanoyl-L-alanyl-D-lactate are obtained.

[0563]¹H-NMR (400 MHz, CDCl₃, δ): 1.46; 1.49 (2d, 6H, 2 x —CH₃; J=7.2Hz); 2.91; 2.92; 2.93 (3s, 9H, 3 x N—CH₃); 3.06 (s, 3H, —N—CH₃); 3.75(s, 3H, —O—CH₃); 4.49; 5.13 (2q, 2H, 2 x CH; J=7.2 Hz) ppm

[0564] EI-MS m/z (%): 317 (M⁺, 1); 286 (M⁺—OMe, 1); 273 (M⁺—CO₂, 7); 214(3); 186 (40); 72 (100).

[0565] Preparation by Process 3c

Example 3 tert-ButylN-methyl-N-trichloroacetylaminocarbonyl-L-alanyl-D-lactate

[0566]

[0567] 2.4 g (12.9 mmol) of trichloroacetyl isocyanate are added at 0°C. to a solution of 3.0 g (12.9 mmol) of tert-butylN-methyl-L-alanyl-D-lactate in 30 ml of acetonitrile, and the mixture isstirred at 0° C. for two hours and then at room temperature for about 18hours. The reaction solution is shaken twice with water, and the organicphase is separated off and concentrated in vacuo after drying oversodium sulphate. The residual crude product is chromatographed on asilica gel column (silica gel 60—Merck, particle size: 0.04 to 0.063 mm)using the eluent cyclohexane:acetone (4:1). 4.2 g (77.2% of theory) oftert-butyl N-methyl-N-trichloro-acetyl-L-alanyl-D-lactate are obtained.

[0568]¹H-NMR (400 MHz, CDCl₃, δ): 1.49; (s, 9H, —O—tBu); 1.40; 1.47;(2d, 6H, 2 x—CH₃; J=6.9 Hz); 2.95 (s, 3H, —N—CH₃); 3.98; 4.22 (2q, 2H, 2x CH; J=6.9 Hz); 9.05 (br., 1H, —CO—NH—CO)ppm

[0569] Preparation by Process 3d

Example 4 tert-Butyl N-butyloxycarbonyl-N-methyl-L-alanyl-D-lactate

[0570]

[0571] 2.0 g (8.6 mmol) of tert-butyl N-methyl-L-alanyl-D-lactate, 2.1 g(15.2 mmol of potassium carbonate and 30 ml of dimethyl sulphoxide aregassed with carbon dioxide for one hour and then treated with 1.2 g (8.6mmol) of butyl bromide. The reaction mixture was stirred at roomtemperature for 48 hours, then separated off from the solid, thevolatile components were stripped off under reduced pressure, theresidue was extracted with chloroform-water and the organic phase wasseparated off. The organic phase is then dried over sodium sulphate andconcentrated in vacuo, and the residual oil is chromatographed on asilica gel column (silica gel 60—Merck, particle size: 0.04 to 0.063mm).

[0572]¹H-NMR (400 MHz, CDCl₃, δ): 1.46; (s, 9H, —O-tBu) ppm EI-MS m/z %:331 (M⁺, 0.5); 275 (M⁺—H₂C═CMe₂, 5); 158 (100).

[0573] Preparation by Process 3e

Example 5 tert-ButylN-methyl-N-(4-nitro-phenoxy)carbonyl-L-alanyl-D-lactate

[0574]

[0575] 6.15 g (47.5 mmol) of N,N-diisopropylethyl-amine (“Hünig's base”)and 4.4 g (21.6 mmol) of 4-nitrophenyl chloroformate are added at 0° C.to a solution of 5.0 g (21.6 mmol) of tert-butylN-methyl-L-alanyl-D-lactate in 150 ml of methylene chloride, and themixture is stirred at 0° C. for two hours and then at room temperaturefor about 18 hours. The reaction solution is shaken twice with water,and the organic phase is separated off and concentrated in vacuo afterdrying over sodium sulphate. The residual crude product ischromatographed on a silica gel column (silica gel 60—Merck, particlesize: 0.04 to 0.063 mm) using the eluent cyclohexane:acetone (10:1).

[0576]¹H-NMR (400 MHz, CDCl₃, δ): 7.31; 8.24 (2d, 4H, 4-NO₂-phenoxy) ppmEI-MS m/z (%): 340 (M⁺—H₂C═CMe₂, 2); 202 (100).

Example 6 tert-Butyl N-methyl-N-morpholinocarbonyl-L-alanyl-D-lactate

[0577]

[0578] 0.65 g (5.0 mmol) of N,N-diisopropylethylamine (“Hünig's base”)and 0.45 g (5.0 mmol) of morpholine are added at room temperature to asolution of 2.0 g (5.0 mmol) of tert-butylN-methyl-N-(4-nitro-phenoxy)carbonyl-L-alanyl-D-lactate in 40 ml ofmethylene chloride, and the mixture is stirred at reflux temperature for18 hours. During the course of this a strong yellow colouration of thereaction mixture occurs. The reaction solution is shaken twice withwater, and the organic phase is separated off and concentrated in vacuoafter drying over sodium sulphate. The residual crude product ischroratographed on a silica gel column (silica gel 60—Merck, particlesize: 0.04 to 0.063 mm) using the eluent cyclohexane:ethyl acetate(1:1).

[0579]¹H-NMR (400 MHz, CDCl₃, δ): 1.42; 1.46 (s/2d, 15H, —O-tBu/-CH₃);2.90 (s, 3H, —N-Me) 3.25 (m, 4H, —CH₂—O—CH₂—); 3.68 (m, 4H,—CH₂—N—CH₂—); 4.69; 4.96 (2q, 2H, -2 x —CH—)ppm

[0580] EI-MS m/z (%): 344 (M⁺, 4); 171 (100).

[0581] Preparation by Process 3f

Example 7 N-methyl-N-trimethylallophanoyl-L-alanyl-D-lactic Acid

[0582]

[0583] Dry hydrogen chloride gas is passed into a solution, cooled to 0°C., of 11.8 g (32.8 mmol) of tert-butylN-methyl-N-trimethylallophanoyl-L-alanyl-D-lactate in 250 ml of absolutemethylene chloride for 20 minutes. The mixture is then stirred at roomtemperature for about 16 hours and the entire reaction mixture isconcentrated in vacuo.

[0584] 10.0 g (100% of theory) ofN-methyl-N-trimethylallophanoyl-L-alanyl-D-lactic acid are obtained,which can be reacted further without further purification.

[0585]¹H-NMR (400 MHz, CDCl₃, δ): 1.46; 1.51 (2d, 2H, 2 x —CH₃; J=7.2Hz); 2.91; 2.94; 3.05 (3s, 12H, 4 x N-Me); 4.84; 5.17 (2q, 2H, —CH—,J=7.2 Hz) ppm EI-MS m/z (%); 304 (MH⁺, 0.1); 259 (2); 214 (1); 186 (15);129 (15); 72 (52); 58 (100).

Example 8N-methyl-N-trimethylallophanoyl-L-alanyl-D-lactyl-L-homoproline MethylEster

[0586]

[0587] 2.8 g (21.8 mmol) of N,N-diisopropylethylamine (“Hünig's base”)and 1.85 g (7.25 mmol) of bis(2-oxo-3-oxa-zolidinyl)-phosphonium acidchloride (BOP-Cl) are added at 0° C. to a solution of 2.0 g (6.6 mmol ofN-methyl-N-trimethylallo-phanoyl-L-alanyl-D-lactic acid and 1.3 g (7.25mmol) of L-homoproline methyl ester hydrochloride (H-Pec-OMe.HCl) in 100ml of methylene chloride and the mixture is stirred at 0° C. for 30minutes, then at room temperature for 18 hours. The reaction solution isshaken twice with water, and the organic phase is separated off andconcentrated in vacuo after drying over sodium sulphate. The residualcrude product is chroma-tographed on a LiChroprep RP-18 column(LiChroprep RP-18—Merck, particle size: 0.04 to 0.063 mm) using theeluent acetonitrile-water (3:7). 0.32 g (11.3% of theory) is obtained.

[0588] EI-MS m/z (%): 428 (M⁺, 2); 397 (2); 352 (17); 186 (38); 72(100).

[0589] The compounds of the general formula (Ia) shown in Table 1 belowcan be prepared analogously to processes 3a-f. TABLE 1 Examples ofcompounds of the formula (Ia) (Ia)

Ex. No. Q G═X R¹ R² R³ R⁴ R⁵ B Physical Data^(a)) 9 H₂C═CH—CH₂—O— C═O—Me —Me —H —H —Me —O-^(t)Bu 316 (MH⁺, 9); 260 (MH⁺- H₂C═CMe₂, 100) 10Me₂CH—CH₂—O— C═O —Me —Me —H —H —Me —O-^(t)Bu 331 (M⁺, 1); 158 (100) 11(Me—CH₂-)₂N— C═O —Me —Me —H —H —Me —O-^(t)Bu 430 (M⁺, 0.2); 100 (100) 12Me—O— C═O —Me —Me —H —H —Me —O-^(t)Bu 290 (MH⁺, 11); 234 (MH⁺- H₂C═CMe₂,100) 13 Me—CH₂—O— C═O —Me —Me —H —Me —O-^(t)Bu 303 (M⁺, 0.2); 247 (M⁺-H₂C═CMe₂, 8) 14 Me—(CH₂)₂—O— C═O —Me —Me —H —H —Me —O-^(t)Bu 317 (M⁺,0.2); 261 (M⁺- H₂C═CMe₂, 8) 15 H₂C═CMe—O— C═O —Me —Me —H —H —Me—O-^(t)Bu 315 (M⁺, 0.2) 16 Cyclohexyl-CH₂—O— C═O —Me —Me —H —H —Me—O-^(t)Bu 371 (M⁺, 0.5; 198 (100) 17 Me₂CH—(CH₂)₂—O— C═O —Me —Me —H —H—Me —O-^(t)Bu 345 (M⁺, 1); 172 (100) 18 Me₂N—CO—NMe— C═O —Me —Me —H —H—Me —O-^(t)Bu 359 (M⁺, 0.6); 72 (100) 19 Me₂CH—O— C═O —Me —Me —H —H —Me—O-^(t)Bu 317 (M⁺, 0.5); 144 (100) 20 Me—CH₂—CHMe—O— C═O —Me —Me —H —H—Me —O-^(t)Bu 331 (M⁺, 0.5); 158 (100) 21 Me₂CH—CH₂—O— C═O —Me —Et —H —H—Me —O-^(t)Bu 345 (M⁺, 0.5; 172 (100) 22 Me₂CH—CH₂—O— C═O —Me —Me —H —H—Me —NMe-nBu 358 (M⁺, 9); 116 (100) 23 Me₂CH—CH₂—O— C═O —Me -sBu —H —H—Me —O-^(t)Bu 373 (M⁺, 0.5); 200 (100) 24 Me—(CH₂)₃—S— C═O —Me —Me —H —H—Me —O-^(t)Bu 347 (M⁺, 3); 174 (100) 25 Me₂CH—CH₂—O— C═O —Me —Me —H —H—H —O-^(t)Bu 317 (M⁺, 0.5); 158 (100) 26 Me₂N—CO—NMe— C═O —Me —H —H —H—Me —O-^(t)Bu 345 (M⁺, 0.1; 72 (100) 27 Me₂CH—CH₂—O— C═O —Me —H —H —H—Me —O-^(t)Bu 1.46 (s, 9H, tBu)^(b)) 28 Me₂N—CO—NMe— CX═O —Me -nPr —H —H—Me —O-^(t)Bu 387 (M⁺, 0.2); 72 (100) 29 Me₂CH—CH₂—O— C═O —Me -nPr —H —H—Me —O-^(t)Bu 304 (M⁺- H₂C═CMe₂, 100) 30 Me₂N—CO—NMe— C═O —Me -nPr —H —H—Me —NMe-sBu 31 Me₂N—CO—NMe— C═O —Me —Me —H —H —Me

370 (M⁺, 0.2); 72 (100) 32 Me₂N—CO—NMe— C═O —Me —Me —H —H —Me

384 (M⁺, 0.2; 340 (M⁺-CO₂, 26); 72 (100) 33 Me₂N—CO—NPr— C═O —Me —Me —H—H —Me

398 (M⁺, 0.5); 72 (100) 34 H₂C═CH—CH₂—O— C═O —Me —Me —H —H —Me

376 (M⁺, 12); 72 (100) 35 Et₂N— C═O —Me —Me —H —H —Me

341 (M⁺, 6); 100 (100) 36 Et₂N— SO₂ —Me —Me —H —H —Me

349 (M⁺; 0.5); 165 (100) 37 Me—CH₂—CHMe—O— C═O —Me —Me —H —H —Me

342 (M⁺, 10); 102 (100) 38 Et₂N—CO—NMe— C═O —Me —Me —H —H —Me

326 (M⁺-72, 28); 100 (100) 39 Et₂N—CO—NMe— C═O —Me —Me —H —H —Me

385 (MH⁺; 0.5); 384 (M⁺; 1); 72 (100) 40 Et₂N—CO—NMe— C═O —Me —Me —H —H—Me

399 (MH⁺; 0.5); 398 (M⁺; 1), 72 (100) 41 Et₂N—CO—NMe— C═O —Me —Me —H —H—Me

398 (M⁺; 0.5); 72 (100) 42 (H₂C═CH—CH₂)₂N— C═O —Me —Me —H —H —Me—O-^(t)Bu 358 (M⁺; 13); 128 (100) 43 (Me₂CH)₂N— C═O —Me —Me —H —H —Me—O-^(t)Bu 44 Me₂N— C═O —Me —Me —H —H —Me —O-^(t)Bu 302 (M⁺; 3); 129(100) 45 Me—CH₂—CHMe—O— C═O —Me —Me —H —H —Me —O—Me 289 (M⁺; 8); 102(100) 46 Me—O— C═O —Me —Me —H —H —Me —O—Me 247 (M⁺; 1); 116 (100) 47Me₂N—CO—NPr— C═O —Me —Me —H —H —Me —O—Me 345 (M⁺; 0.5); 72 (100) 48Et₂N—CO—NMe— C═O —Me —Me —H —H —Me —O—Me 346 (M⁺+H; 44); 100 (100) 49Et₂N— C═O —Me —Me —H —H —Me —O—Me 288 (M⁺; 2); 100 (100) 50H₂C═CH—CH₂—O— C═O —Me —Me —H —H —Me —O—Me 273 (M⁺; 12); 142 (100) 51Phenyl-O— C═O —Me —Me —H —H —Me —O-^(t)Bu 295 (M⁺; H₂C═CMe₂; 3); 202(100) 52 H₂C═CMe—CH₂— SO₂ —Me —Me —H —H —Me —O-^(t)Bu 350 (M⁺+H; 5); 294(71); 176 (100) 53 F₂C═CF—CH₂—CH₂—O— C═O —Me —Me —H —H —Me —O-^(t)Bu 383(M⁺+5); 210 (100) 54 H₂C═CH—CH₂—O— C═O —Me -iBu —H —H —Me —O-^(t)Bu 358(M⁺+H, 10) 184 (100 55 H₂C═CH—CH₂—O— C═O —Me -iBu —H —H —Bn —O-^(t)Bu434 (M⁺+H, 8); 184 (100 56 Benzyl-O— C═O —Me —Bn —H —H -iBu —O—Me 57tBu—O— C═O —H 1'Bn —H —H -iPr

232 (M⁺+H; 38); 100 (100) 58 H₂C═CH—CH₂—O— C═O —Me —Me —H —H —Me

328 (m⁺; 5); 142 (100) 59 H₂C═CH—CH₂—O— C═O —Me —Me —H —H —Me

341 (M⁺; 22); 70 (100) 60 H₂C═CH—CH₂—O— C═O —Me —Me —H —H —Me

440 (M⁺; 2); 340 (100) 61 H₂C═CH—CH₂—O— C═O —Me —Me —H —H —Me

454 (M⁺; 12); 340 (100) 62 H₂C═CH—CH₂—O— C═O —Me —Me —H —H —Me —NMe—O—Me302 (M⁺; 0.5); 142 (100) 63 H₂C═CH—CH2-O— C═O —Me —Me —H —H —Me—NMe(CH₂)₂—NMe₂ 343 (M⁺; 0.5); 58 (100) 64 H₂C═CH—CH2-O— C═O —Me —Me —H—H —Me

363 (M⁺; 32); 142 (100) 65 H₂C═CH—CH₂—O— C═O —Me —Me —H —H —Me

399 (M⁺; 2); 142 (100) 66 H₂C═CH—CH—O— C═O —Me —Me —H —H —Me

404 (M⁺; 52); 107 (100)= 67 H₂C═CH—CH₂—O— C═O —Me —Me —H —H —Me

404 (M⁺; 7); 133 (100) 68 H₂C═CH—CH2_(O)- C═O —Me —Me —H —H —Me

405 (M⁺; 33); 142 (100) 69 tBu—O— C═O —Me —Me —H —H —Me —O—Bn 365 (M⁺;0.5); 58 (100) 70 tBu—O— C═O —Me —Me —H —H —Me —OH 275 (M⁺; ); 58 (100)71 tBu—O— C═O —Me —Me —H —H —Me

341 (MH⁺; 100); 141 (38) 72 tBu—O— C═O —Me —Me —H —H —Me

384 (MH⁺; 100); 141 (47) 73 tBu—O— C═O —Me —Me —H —H —Me

434 (MH⁺; 100); 141 (59) 74 tBu—O— C═O —Me —Me —H —H —Me

414 (MH⁺; 100); 141 (43) 75 Me₂N—CO—NMe— C═O —Me —Me —H —H —Me

449 (M⁺; 22); 79 (100)) 76 tBu—O— C═O —Me —Me —H —H —Me

344 (MH⁺; 100); 244 (44) 77 H₂C═CH—CH₂—O— C═O —Me —Me —H —H —Me

78 H₂C═CH—CH₂—O— C═O —Me —Me —H —H —Me

369 (M⁺; 19); 354 (M⁺−Me, 100) 79 H₂C═CH—CH₂—O— C═O —Me —Me —H —H —Me

385 (M⁺; 1); 340 (100)( 80 H₂C═CH—CH₂—O— C═O —Me —Me —H —H —Me

461 (M⁺; 12); 135 (100) 81 H₂C═CH—CH₂—O— C═O —Me —Me —H —H —Me

438 (M⁺; 1); 340 (100) 82 H₂C═CH—CH₂—O— C═O —Me —Me —H —H —Me

83 H₂C═CH—CH₃—O— C═O —Me —Me —H —H —Me

84 H₂C═CH—CH₂—O— C═O —Me —Me —H —H —Me

85 tBu—O— C═O —Me —Me —H —H —Me

86 H₂C═CH—CH₂—O— C═O —Me —Me —H —H —Me

426 (M⁺; 5); 100 (100) 87 tBu—O— C═O —Me —Me —H —H —Me

443 (M⁺; 4); 58 (100) 88 H₂C═CH—CH₂—O— C═O —Me —Me —H —H —Me

419 (M⁺; 100); 204 (22) 89 H₂═CH—CH₂—O— C═O —Me —Me —H —H —Me

340 (M⁺; 8); 142 (100) 90 H₂C═CH—CH₂—O— C═O —Me —Me —H —H —Me

312 (M⁺; 9); 142 (100) 91 H₂C═CH—CH₂—O— C═O —Me —Me —H —H —Me

419 (M⁺; 17); 141 (4) 92 H₂C═CH—CH₂—O— C═O —Me —Me —H —H —Me

409 (M⁺; 25); 124 (100) 93 Me₂N— C═O —Me —Me —H —H —Me —O—Me 261 (M⁺;1); 72 (100) 94 Me₂N— SO₂ —Me —Me —H —H —Me —O—Me 296 (M⁺; 2); 165 (100)95

C═O —Me —Me —H —H —Me —O—Me 302 (M⁺; 1); 114 (100) 96 Me—O—CO— C═O —Me—Me —H —H —Me —O—Me 275 (M⁺; 3); 144 (100) 97 H₂C═CMe—CH₂— SO₂ —Me —Me—H —H —Me —O—Me 98

SO₂ —Me —Me —H —H —Me —O—Me 336 (M²; 2); 205 (100) 99

C═O —Me —Me —H —H —Me —O—Me 359 (M⁺; 1); 114 (100) 100 Me₂N—CO—NEt— C═O—Me —Me —H —H —Me —O—Me 331 (M⁺; 1); 72 (100) 101

SO₂ —Me —Me —H —H —Me —O—Me 338 (M⁺; 3); 217 (100) 102 Me₂N—CO—NEt— C═O—Me —Me —H —H —Me

385 (M⁺; 1); 72 (100) 103

C═O —Me —Me —H —H —Me

412 (M⁺; 1); 114 (100) 104

SO₂ —Me —Me —H —H —Me

392 (MH⁺; 100); 207 (28) 105 H₂C═CH—CH₂—O— C═O —Me -iPr —H —H —Me

354 (M⁺; 2); 170 (100) 106 Me₂N—CO—NMe— C═O —Me -iPr —H —H —Me

399 (M⁺; 0.5); 72 (100) 107 H₂C═CH—CH₂—O— C═O —Me —Bn —H —H —Me

402 (M⁺; 16); 139 (100) 108 Me₂N—CO—NMe— C═O —Me —Bn —H —H —Me

446 (M⁺; 0.5); 72 (100) 109 H₂C═CH—CH₂O— C═O —Me -sBU —H —H -iPr

396 (M⁺; 2); 184 (100) 110 Me₂N—CO—NMe— C═O —Me -sBU —H —H -iPr

111 Cl—CHMe—O— C═O —Me —Me —H —H —Me —O—Me 295 (M⁺; 2); 164 (100) 112Ac—O—CHMe—O— C═O —Me —Me —H —H —Me —O—Me 113 Me₂N—CO—NMe— C═O —Me —Me —H—H —Me

485 (M⁺; 2); 72 (100) 114 Me₂N—CO—NMe— C═O —Me —Me —H —H —Me

115 Me₂N—CO—NMe— C═O —Me —Me —H —H —Me

[0590] Starting Substances of the Formula (I)

Example (I-1) N-Benzyl-N-methyl-L-alanyl-D-lactic Acid Piperidide

[0591]

[0592] 5.4 g (41.4 mmol) of N,N-diisopropylethylamine (Hünig's base) and5.3 g (20.7 mmol) of bis(2-oxo-3-oxazolidinyl)-phosphonium acid chloride(BOP-Cl) are added at 0° C. to a solution of 5.0 g (18.8 mmol) ofN-benzyl-N-methyl-L-alanyl-D-lactic acid and 1.6 g (20.7 mmol) ofpiperidine in 150 ml of methylene chloride, and the mixture is stirredat 0° C. for two hours and then at room temperature for 18 hours. Theresidual crude product is chromatographed on a silica gel column (silicagel 60—Merck, particle size: 0.04 to 0.063 mm) using the eluentcyclohexane:ethyl acetate (3:1). 3.5 g (55.8% of theory) ofN-benzyl-N-methyl-L-alanyl-D-lactic acid piperidide are obtained.

[0593] EI-MS m/z (%): 332 (M⁺, 1); 213 (2); 192 (2); 148 (100); 120(35); 91 (55)

Example (I-2) Methyl-L-alanyl-D-lactic Acid Piperidide

[0594]

[0595] 3.3 g (9.9 mmol) of N-benzyl-N-methyl-L-alanyl-D-lactic acidpiperidide are hydrogenated in 100 ml of ethanol in the presence of 0.35g of Pd(OH)₂-carbon [20% Pd content] until absorption of hydrogen iscomplete (about 4 hours). After filtering off the catalyst, the entirereaction solution is concentrated in vacuo. 2.4 g (100% of theory) ofN-methyl-L-alanyl-D-lactic acid piperidide are obtained.

[0596] GC-MS m/z (%): 243 (MH⁺, 100); 158 (32)

Example (I-3) Methyl N-benzyl-N-methyl-L-alanyl-D-lactate

[0597]

[0598] The coupling reaction is carried out analogously to the reactionprocedure of Example 1 using:

[0599] 18.5 g (95.7 mmol) of N-benzyl-N-methyl-L-alanine,

[0600] 10.0 g (95.7 mmol) of methyl (R)-(+)-lactate,

[0601] 300 ml of absol. methylene chloride,

[0602] 36.7 g (284.5 mmol) of N,N-diisopropylethylamine (“Hünig'sbase”),

[0603] 29.0 g of bis(2-oxo-3-oxazolidinyl)-phosphonium acid chloride(BOP-Cl).

[0604] The residual crude product is chromatographed on a silica gelcolumn (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using theeluent cyclohexane:ethyl acetate (3:1). 5.6 g (20.9% of theory of methylN-benzyl-N-methyl-L-alanyl-D-lactate are obtained.

[0605] EI-MS m/z (%): 279 (M⁺, 11); 148 (Ph—CH₂—NMe-CHMe, 100); 91(Ph—CH₂—, 99).

[0606] The starting substances of the general formula (I) shown in Table2 below can be prepared analogously to examples (I-1) to (I-3). TABLE 2Examples of compounds of the formula (I)

Ex. No. A R¹ R² R³ R⁴ R⁵ B Physical Data^(a)) I-4 —CO—O-Benzyl —Me —Me—H —H —Me —O-^(t)Bu I-5 —CO—O-Benzyl —Me —Me —H —H —Me —OH I-6—CO—O-Benzyl —Me —H —H —H —Me —O-^(t)Bu I-7 —CO—O-Benzyl —Me —H —H —H—Me —OH I-8 —CO—O-^(t)Bu —Me —CHMe —H —H —Me —O—Bn (O—Bn) I-9 -Benzyl—Me —Me —H —H —Me —NMe-nBu 334 (M⁺, 7); 148 (100) I-10 —H —Me —Me —H —H—Me —NMe-nBu 244 (M⁺, 0.5); 58 (100) I-11 -Benzyl —Me —Me —H —H —Me—O-iBu 448 (M⁺, 1); 148 (100) I-12 —H —Me —Me —H —H —Me —O-iBu 232 (MH⁺,100) I-13 -Benzyl —Me —Me —H —H —Me —NMe-sBu 334 (M⁺, 1); 148 (100) I-14—H —Me —Me —H —H —Me —NMe-sBu I-15 -Benzyl —Me —Me —H —H —Me

346 (M⁺, 1); 148 (100) I-16 —H —Me —Me —H —H —Me

257 (MH⁺, 100) I-17 —H —Me —Me —H —H —Me —O—Me 3,76 (s, 3H, —O—Me)^(b))I-18 -Benzyl —Me —Me —H —H —Me

360 (M⁺, 4); 148 (100) I-19 —H —Me —Me —H —H —Me

I-20 -Benzyl —Me —Me —H —H —Me

360 (M⁺, 3); 148 (100) I-21 —H —Me —Me —H —H —Me

271 (MH⁺, 2); 58 (100) I-22 -Benzyl —Me —Me —H —H —Me

346 (M⁺, 2); 148 (100) I-23 —H —Me —Me —H —H —Me

I-24 -Benzyl —Me -iBu —H —H —H —O-^(t)Bu 350 (M⁺+H, 16); 190 (100) I-25-Benzyl —Me -iBu —H —H —H —OH 272 (M⁺−21); 100 (100) I-26 —H —Me -iBu —H—H —H —O-^(t)Bu 260 (M⁺+H, 100); 204 (74) I-27 -Benzyl —Me -iBu —H —H —H—O—Me 306 (M⁺−H, 20); 307 (M⁺, 16); 91 (100) I-28 -Benzyl —Me -iBu —H —H—H —O—Et I-29 -Benzyl —Me -iBu —H —H —Bn —OH 384 (M⁺+H, 42); 91 (100)I-30 -Benzyl —H -iBu —H —H —Me —O-^(t)Bu 350 (M⁺+H, 100); 348 (20) I-31-Benzyl —Me -iBu —H —H —Bn —O—Me 348 (M⁺+H, 17); 396 (M−H, 18), 190(100) I-32 -Benzyl —H -iBu —H —H —Me —OH 294 (M⁺+H, 36); I-33 —H —Me-iBu —H —H —Bn —O—Me 308 (M⁺+H, 100) I-34 —H —H -iBu —H —H —Bn —O—MeI-35 -Benzyl —Me -iBu —H —H —Me —O—Me 322 (M⁺+H, 16); 320 (M⁺−H, 26);190 (100) I-36 —H —Me -iBu —H —H —Me —O—Me 232 (M⁺+H, 38); 100 (100)I-37 -Benzyl —H -nPr —H —H —Me —O-^(t)Bu 336 (M⁺+H, 100) I-38 -Benzyl —H-nPr —H —H —Me —OH 280 (M⁺+H, 100); 91 (62) I-39 —H —H -nPr —H —H —Me—O-^(t)Bu 199 (M⁺−46, 96); 72 (100) I-40 -Benzyl —Me -nPr —H —H —Me—O-^(t)Bu 350 (M⁺+H, 16); 348 (20); 176 (100) I-41 -Benzyl —Me -nPr —H—H —Bn —O-^(t)Bu 426 (M⁺+H, 17); 414 (M⁺−H, 19); 179 (100) I-42—CO—O-^(t)Bu

—H —H —H —O-^(t)Bu 348 (M⁺+H, 17); 346 (M⁺−H, 16); 236 (100) I-43 —H

—H —H —H —OH 192 (M⁺+H, 90); 134 (100) I-44 —CO—O-^(t)Bu

—H —H —Me —O-^(t)Bu 360 (M⁺+H, 92); 304 (100) I-45 —H

—H —H —Me —OH 204 (M⁺+H, 100); 190 (32) I-46 —CO—O-^(t)Bu —(CH₂)₃— —H —H—Bn —O-^(t)Bu 420 (M⁺+H, 94); 364 (100) I-47 —H —(CH₂)₃— —H —H —Me —OH188 (M⁺+H, 100) I-48 —CO—O-^(t)Bu —(CH₂)₃— —H —H —Me —O-^(t)Bu 344(M⁺+H, 100); 288 (76) I-49 —CO—O-^(t)Bu —(CH₂)₄— —H —H —Bn —O-^(t)Bu 434(M⁺+H, 20); 334 (100) I-50 —H —(CH₂)₄— —H —H —Bn —OH 278 (M⁺+H, 100)I-51 —CO—O-Benzyl —H -iBu —H —H —H —OH 322 (M⁺+H, 40); 156 (100) I-52-Benzyl —Me —Me —H —H —Me

334 (M⁺; 1); 148 (100) I-53 —H —Me —Me —H —H —Me

I-54 -Benzyl —Me —Me —H —H —Me

347 (M⁺; 0.66); 148 (100) I-55 —H —Me —Me —H —H —Me

257 (M⁺; 5); 58 (100) I-56 -Benzyl —Me —Me —H —H —Me

330 (M⁺; 1); 148 (100) I-57 -Benzyl —Me —Me —H —H —Me

446 (M⁺; 1.14); 346 (70); 148 (100); 100 (92) I-58 —H —Me —Me —H —H —Me

356 (M⁺; 1); 256 (35); 100 (100); 58 (66) I-59 -Benzyl —Me —Me —H —H —Me

460 (M⁺; 0.45); 341 (38); 148 (100); 91 (53) I-60 —H —Me —Me —H —H —Me

370 (M⁺; 20); 256 (41); 148 (40); 58 (100) I-61 -Benzyl —Me —Me —H —H—Me —NMe—OMe 308 (M⁺; 2); 148 (100) I-62 —H —Me —Me —H —H —Me —NMe—OMe218 (M; 0.5); 58 (100) I-63 -Benzyl —Me —Me —H —H —Me

349 (M⁺; 0.24); 148 (100) I-64 —H —Me —Me —H —H —Me

I-65 -Benzyl —Me —Me —H —H —Me

346 (M⁺, 0.5); 148 (100) I-66 —H —Me —Me —H —H —Me

256 (M, S); 58 (100) I-67 -Benzyl —Me —Me —H —H —Me

403 (M⁺; 0.5); 148 (100); 91 (52) I-68 —H —Me —Me —H —H —Me

276 (M⁺, 0.5); 121 (32); 58 (100) I-69 -Benzyl —Me —Me —H —H —Me

404 (M⁺; 0.28); 346 (M⁺−(CH₂)₂—NMe₂; 62); 285 (60); 148 (100) I-70 —H—Me —Me —H —H —Me

314 (M⁺; 0.5); 58 (100) I-71 -Benzyl —Me —Me —H —H —Me

410 (M⁺; 1); 291 (50); 148 (100); 91 (55) I-72 —H —Me —Me —H —H —Me

I-73 -Benzyl —Me —Me —H —H —Me

410 (M⁺; 0.24); 291 (32); 148 (100); 91 (42) I-74 —H —Me —Me —H —H —Me

I-75 -Benzyl —Me —Me —H —H —Me

405 (M⁺; 1); 148 (100); 91 (41) I-76 —H —Me —Me —H —H —Me

315 (M⁺; 0.5); 58 (100) I-77 -Benzyl —Me —Me —H —H —Me

489 (M⁺; 1); 148 (100); 91 (40) I-78 —H —Me —Me —H —H —Me

I-79 -Benzyl —Me —Me —H —H —Me

411 (M⁺; 0.5); 148 (100) I-80 —H —Me —Me —H —H —Me

321 (M⁺; 8); 58 (100) I-81 -Benzyl —Me —Me —H —H —Me

433 (MH⁺; 100); 141 (12) I-82 —H —Me —Me —H —H —Me

343 (MH⁺; 100); 141 (11) I-83 -Benzyl —Me —Me —H —H —Me

376 (MH⁺; 100); 141 (14) I-84 —H —Me —Me —H —H —Me

286 (MH⁺; 100); 201 (22) I-85 -Benzyl —Me —Me —H —H —Me

392 (MH⁺; 100); 141 (22) I-86 —H —Me —Me —H —H —Me

302 (MH⁺; 100); 217 (20) I-87 -Benzyl —Me —Me —H —H —Me

468 (MH⁺; 100); 141 (19) I-88 —H —Me —Me —H —H —Me

378 (MH⁺; 100); 244 (42) I-89 -Benzyl —Me —Me —H —H —Me

445 (MH⁺; 100); 141 (18) I-90 —H —Me —Me —H —H —Me

355 (MH⁺; 100); 141 (4) I-91 —H —Me —Me —H —H —Me

342 (NH⁺; 1); 58 (100) I-92 —H —Me —Me —H —H —Me

241 (MH⁺; 100) 141 (4) I-93 —H —Me —Me —H —H —Me

284 (MH⁺; 100); I-94 —H —Me —Me —H —H —Me

314 (MH⁺; 100); I-95 -Benzyl —Me —Me —H —H —Me

425 (M⁺; 13); 148 (100) I-96 —H —Me —Me —H —H —Me

335 (M⁺; 60); 250 (100) I-97 -Benzyl —Me —Me —H —H —Me

425 (M⁺; 1); 148 (100) I-98 -Benzyl —Me —Me —H —H —Me

426 (M⁺; 1); 148 (100) I-99 -Benzyl —Me —Me —H —H —Me

426 (M⁺; 4); 148 (100) I-100 -Benzyl —Me —Me —H —H —Me

415 (M⁺; 0.5); 148 (100) I-101 —H —Me —Me —H —H —Me

325 (M⁺; 6); 124 (100) I-102 -Benzyl —Me —Me —H —H —Me

346 (M⁺; 2); 148 (100) I-103 —H —Me —Me —H —H —Me

257 (MH⁺; 98); 172 (100) I-104 -Benzyl —Me —Me —H —H —Me

318 (M⁺; 2); 148 (100) I-105 —H —Me —Me —H —H —Me

229 (MH⁺; 100); 144 (34) I-106 -Benzyl —Me -iPr —H —H —Me

360 (M⁺; 2); 176 (100) I-107 —H —Me -iPr —H —H —Me

I-108 -Benzyl —Me —Bn —H —H —Me

408 (M⁺; 1); 91 (100) I-109 —H —Me —Bn —H —H —Me

318 (M⁺; 0.5); 134 (100) I-110 -Benzyl —Me -sBu —H —H -iPr

402 (M⁺; 3); 190 (100) I-111 —H —Me -sBu —H —H -iPr

313 (MH⁺; 1); 112 (100) I-112 -Benzyl —Me —Me —H —H —Me

447 (M⁺; 3); 148 (100) I-113 —H —Me —Me —H —H —Me

358 (MH⁺; 100); 302 (55) I-114 -Benzyl —Me —Me —H —H —Me —O—Et 293 (M⁺;1); 148 (100)

1. Use of didepsipeptides of the general formula (I) and their salts

in which R¹ represents hydrogen, straight-chain or branched alkyl,cycloalkyl, arylalkyl, aryl, heteroaryl, heteroaryalkyl, each of whichis optionally substituted R¹ and R² together with the atoms to whichthey are bonded represent a 5- or 6-membered ring which can optionallybe interrupted by oxygen, sulphur, sulphoxyl or sulphonyl and isoptionally substituted, R² and R³ independently of one another representhydrogen, straight-chain or branched alkyl, alkenyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each ofwhich is optionally substituted, or R² and R³ together represent aspirocyclic ring, which is optionally substituted, R⁴ and R⁵independently of one another represent hydrogen, straight-chain orbranched alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aryalkyl,heteroaryl, heteroarylalkyl, each of which is optionally substituted, orR⁴ and R⁵ togther represent a spirocyclic ring, which is optionallysubstituted, A represents hydrogen, alkyl, aralkyl, formyl,alkoxydicarbonyl or a radical of the group G¹

 in which

 can denote carboxyl, thiocarboxyl, —CH═CH—NO₂, —CH═CH—CN, —C═N—R⁶,sulphoxyl, sulphonyl, —P(O)—OR⁷ or P(S)—OR⁷, R⁶ represents hydrogen,hydroxyl, alkoxy, alkylcarbonyl, halogenoalkycarbonyl, alkylsulphonyl,nitro or cyano, and R⁷ represents hydrogen or alkyl, and Q representsstraight-chain or branched alkyl, alkenyl, alkinyl, cycloalkyl, aryl,arylalkyl, hetaryl or hetarylalkyl, each of which is optionallysubstituted, or optionally represents a radical from the group G² and G³

 in which

 can denote carboxyl, thiocarboxyl or sulphonyl, Y represents oxygen,sulphur or —NR⁹, R⁸ in the case where Y represents nitrogen can denote acyclic amino group linked via a nitrogen atom, R⁸ and R⁹ independentlyof one another represent hydrogen, straight-chain or branched alkyl,alkenyl, alkinyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, hetaryl,hetarylalkyl, each of which is optionally substituted, or R⁸ and R⁹together with the adjacent N atom, [lacuna] a carbocyclic 5-, 6- or7-membered ring system or a 7 to 10-membered bicyclic ring system whichcan optionally also be interrupted by oxygen, sulphur, sulphoxyl,sulphonyl, carbonyl, —N—O—, —N═, —NR¹¹— or by quaternized nitrogen andis optionally substituted, R¹⁰ represents hydrogen or alkyl, R¹¹represent represents hydrogen, straight-chain or branched alkyl,alkenyl, alkinyl, cycloalkyl, cycloalkylalkyl, alkoxycarbonyl,alkylcarbonyl, cycloalkylcarbonyl, cyano, aryl, arylalkyl, hetaryl,hetarylalkyl, each of which is optionally substituted, and B representrepresents hydroxyl, alkoxy, alkenyloxy, alkinyloxy, cycloalkyloxy,cycloalkylalkyloxy, aryloxy-, arylalkyloxy, hetaryloxy, hetarylalkyloxy,each of which is optionally substituted, or  represents the radicals—NR¹²R¹³, —NR¹⁴—NR¹²R¹³ and —NR¹⁵—OR¹⁶,  in which R¹² and R¹³independently of one another represent hydrogen, straight-chain orbranched alkyl, alkylcarbonyl, alkyl sulphonyl, alkenyl, alkinyl,cycloalkyl, cycloalkylalkyl, aryl, arylcarbonyl, arylsulphonyl,arylalkyl, hetaryl, hetarylcarbonyl, hetarylsulphonyl or hetarylalkyl,each of which is optionally substituted, or R¹² and R¹³ together withthe adjacent N atom [lacuna] a carbocyclic 5-, 6-, 7- or 8-membered ringsystem or a 7 to 10-membered bicyclic ring system which can optionallyalso be interrupted by oxygen, sulphur, sulphoxyl, sulphonyl, carbonyl,—N—O, —N═, —NR¹¹— or by quaternized nitrogen and is optionallysubstituted, R¹⁴ represents hydrogen, straight-chain or branched alkyl,cycloalkyl, arylalkyl or hetarylalkyl, each of which is optionallysubstituted, R¹⁵ and R¹⁶ independently of one another denote hydrogen,straight-chain or branched alkyl, alkylcarbonyl, alkenyl, alkinyl,cycloalkyl, cycloalkylalkyl, arylalkyl or hetarylalkyl, each of which isoptionally substituted, R¹⁵ and R¹⁶ together with the adjacent N—O-grouprepresent a carbocyclic 5-, 6- or 7-membered ring, and their opticalisomers and racemates, for the control of endoparasites in medicine andveterinary medicine.
 2. New didepsipeptides of the general formula (Ia )and their salts

in which R¹ represents hydrogen, straight-chain or branched C₁₋₄-alkyl,C₃₋₆-cycloalkyl, aryl-C₁₋₂-alkyl or hetaryl-C₁₋₂-alkyl, each of which isoptionally substituted, and R¹ and R² together with the atoms to whichthey are bonded represent a 5- or 6-membered ring which can optionallybe interrupted by oxygen, sulphur, sulphoxyl or sulphonyl and isoptionally substituted, R² represents hydrogen, straight-chain orbranched alkyl having up to 6 carbon atoms, alkenyl having up to 4carbon atoms, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₂-alkyl, aryl,aryl-C₁₋₂-alkyl, hetaryl, hetaryl-C₁₋₂-alkyl each of which is optionallysubstituted, R³ and R⁴ represent hydrogen, R⁵ represents hydrogen,straight-chain or branched alkyl having up to 6 carbon atoms, alkenylhaving up to 4 carbon atoms, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₂-alkyl, aryl, aryl-C₁₋₂-alkyl, hetaryl,hetaryl-C₁₋₂-alkyl each of which is optionally substituted,

 represents carboxyl, thiocarboxyl, —C═CH—NO₂, —C═CH—CN, —C═N—R⁶,sulphoxyl, sulphonyl, —P(O)—OR⁷ or P(S)—OR⁷, R⁶ represents hydrogen,hydroxyl, C₁₋₄-alkoxy, C₁₋₄-alkylcarbonyl, C₁₋₄-halogenoalkylcarbonyl,C₁₋₄-alkylsulphonyl, nitro or cyano, and R⁷ represents hydrogen orC₁₋₄-alkyl, and Q represents straight-chain or branched C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkinyl, C₃₋₆-cycloalkyl or hetaryl-C₁₋₂-alkyl, eachof which is optionally substituted, or optionally represents a radicalfrom the group G² and G³

 in which

 can denote carboxyl, thiocarboxyl or sulphonyl, Y represents oxygen,sulphur or —NR⁹, R⁸ in the case where Y represents nitrogen can denote acyclic amino group linked via a nitrogen atom, R⁸ and R⁹ independentlyof one another represents hydrogen, straight-chain or branchedC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkinyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₂-alkyl, hetaryl or hetaryl-C₁₋₂-alkyl, each of whichis optionally substituted, or R⁸ and R⁹ together with the adjacent Natom represent a carbocyclic 5-, 6- or 7-membered ring system or a 7 to10-membered bicyclic ring system which can optionally also beinterrupted by oxygen, sulphur, sulphoxyl, sulphonyl, carbonyl, —N—O—,—N═, —NR¹¹— or by quaternized nitrogen and is optionally substituted,R¹⁰ represents hydrogen or C₁₋₄-alkyl, and R¹¹ represents hydrogen,straight-chain or branched C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₂₋₆-alkenyl,C₂₋₆-alkinyl, C₃₋₆-cycloalkyl, C₃₋₆-cyclo-alkyl-C₁₋₂-alkyl,C₁₋₄-alkoxycarbonyl, C₁₋₄-alkylcarbonyl, C₃₋₆-cycloalkylcarbonyl, cyano,aryl, aryl-C₁₋₂-alkyl, hetaryl or hetaryl-C₁₋₂-alkyl, each of which isoptionally substituted, and B represents C₁₋₆-alkoxy, C₂₋₆-alkenyloxy,C₂₋₆-alkinyloxy, C₃₋₇-cycloalkyloxy, C₃₋₇-cycloalkyl-C₁₋₂-alkyloxy,aryloxy-, aryl-C₁₋₂-alkyloxy, hetaryloxy, hetaryl-C₁₋₂-alkyloxy, each ofwhich is optionally substituted, or  represents the amino radicals—NR¹²R¹³, —NR¹⁴—NR¹²R¹³ and —NR¹⁵—OR¹⁶, in which R¹² and R¹³independently of one another represent hydrogen, straight-chain orbranched C₁₋₆-alkyl, C₁₋₆-alkylcarbonyl, C₁₋₆-alkylsulphonyl,C₂₋₆-alkenyl, C₂₋₆-alkinyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₂-alkyl,aryl, arylcarbonyl, arylsulphonyl, aryl-C₁₋₂-alkyl, hetaryl,hetarylcarbonyl, hetarylsulphonyl or hetaryl-C₁₋₂-alkyl, each of whichis optionally substituted, or R¹² and R¹³ together with the adjacent Natom represent a carbocyclic 5-, 6-, 7- or 8-membered ring system or a 7to 10-membered bicyclic ring system, which can optionally also beinterrupted by oxygen, sulphur, sulphoxyl, sulphonyl, carbonyl, —N—O,—N═, —NR¹¹— or by quaternized nitrogen and is optionally substituted,R¹⁴ represents hydrogen, straight-chain or branched C₁₋₆-alkyl,C₃₋₆-cycloalkyl, each of which is optionally substituted, R¹⁵ and R¹⁶independently of one another denote hydrogen, straight-chain or branchedC₁₋₆-alkyl, C₁₋₆-alkylcarbonyl, C₂₋₆-alkenyl, C₂₋₆-alkinyl orC₃₋₆-cycloalkyl, each of which is optionally substituted, and R¹⁵ andR¹⁶ together with the adjacent N—O-group represent a carbocyclic 5-, 6-or 7-membered ring, with the proviso in the case where in formula (Ia)R¹, R⁵ and ═G═X together represent the following radicals: R¹ representshydrogen and methyl, R⁵ represents hydrogen,

 represents carboxyl, the radicals Q and B must fulfil the followingcondition: Q represents radicals other than methyl, B representsradicals other than —NH₂, and with the proviso in the case where informula (Ia) G² and ═G═X together represent the following radicals:

 represents carboxyl, G² represents tert-butyloxy, benzyloxy and4-nitro-benzyloxy, the radical B represents radicals other thantert-butyloxy, benzyloxy and 4-nitro-benzyloxy, and their optionalisomers and racemates.
 3. Process for the preparation of the newdidepsipeptides of the general formula (Ia) and their salts according toclaim 2

in which the radicals R¹, R², R³, R⁴, R⁵, G, Q, X and B have the meaningindicated in claim 2, characterized in that a) N-terminal-substitutedamino acids of the general formula (II)

 in which the radicals R¹, R², R³, G, Q, and X have the meaningindicated in claim 2, or their carboxyl-activated derivatives or theiralkali metal salts, are reacted, if appropriate in the presence of acatalyst, if appropriate in the presence of an acid-binding agent and ifappropriate in the presence of a diluent, with carboxylic acidderivatives of the general formula (III)

 in which the radicals R⁴, R⁵ and B have the meaning indicated in claim2 and Z represents a suitable leaving group for example halogen such asbromine, chlorine fluorine, or hydroxyl, or b) N-terminal-deblockeddidepsipeptides of the general formula (Ib)

 in which the radicals R¹, R², R³, R⁴, R⁵ and B have the meaningindicated in claim 2, are reacted, if appropriate in the presence of acatalyst, if appropriate in the presence of an acid-binding agent and ifappropriate in the presence of a diluent, with compounds of the generalformula (IV)

 in which the radicals G, Q, W and X have the meaning indicated in claim2 and W represents a suitable leaving group, for example halogen,alkoxy, alkylthio or aryloxy, or c) N-terminal-deblocked didepsipeptidesof the general formula (Ib)

 in which the radicals R¹, R², R³, R⁴, R⁵ and B have the meaningindicated in claim 2, are reacted, if appropriate in the presence of acatalyst, if appropriate in the presence of an acid-binding agent and ifappropriate in the presence of a diluent, with compounds of the generalformulae (V) or (VI)

 in which the radicals R⁸, G¹, X, X¹ and Y have the meaning indicated inclaim 2, or for the preparation of the depsipeptides of the generalformula (Ia) and their salts in which the group

 represents carboxyl and Y represents oxygen, d) N-terminal-deblockeddidepsipeptides of the general formula (Ib)

 in which the radicals R¹, R², R³, R⁴, R⁵ and B have the meaningindicated in claim 2, are reacted in a first reaction step with carbondioxide and an alkali metal carbonate of the formula (VII) M₂CO₃  (VII) in which M represents a monovalent alkali metal cation, preferablylithium, sodium, potassium or caesium, in particular potassium orcaesium, then in a second reaction step the resulting alkali metal saltof the formula (VIII)

 in which the radicals R¹, R², R³, R⁴, R⁵ and B have the meaningindicated in claim 2, M represents a metal cation equivalent bound likea salt, is reacted with alkylating agents of the formula (IX)R⁸-Hal  (IX)  in which R⁸ has the meaning indicated in claim 2 and Halrepresents a halogen such as fluorine, chlorine, bromine or iodine, ifappropriate in the presence of a diluent and if appropriate in thepresence of a basic reaction auxiliary, or e) didepsipeptides of thegeneral formula (Ic)

 in which the radicals R¹, R², R³, R⁴, R⁵, G, W, X and B and have themeaning indicated in claim 2 and 3b, are reacted, if appropriate in thepresence of a catalyst, if appropriate in the presence of anacid-binding agent and if appropriate in the presence of a diluent, withcompounds of the general formula (X) R⁸—Y—H  (X)  in which the radicalsR⁸ and Y have the meaning indicated above in claim 2, or f)didepsipeptides of the general formula (Id)

 in which the radicals R¹, R², R³, R⁴, R⁵, G, Q, X and B have themeaning indicated in claim 2 or their carboxyl-activated derivatives ortheir alkali metal salts are reacted, if appropriate in the presence ofa catalyst, if appropriate in the presence of an acid-binding agent andif appropriate in the presence of a diluent, with compounds of thegeneral formula (XI) H—B  (XI)  in which the radical B has the meaningindicated above in claim
 2. 4. Endoparasiticidal compositions,characterized in that they contain at least one didepsipeptide of theformula (I) according to claim
 1. 5. Process for the production ofendoparasiticidal compositions, characterized in that didepsipeptides ofthe formula (I) according to claim 1 are mixed with extenders and/orsurface-active agents.
 6. Use of didepsipeptides of the formula (I)according to claim 1 for the production of endoparasiticidalcompositions.